Certain heteroaryl diazacycloalkanes as cholinergic ligands at nicotinic acetylcholine receptors

ABSTRACT

The present invention discloses compounds of formula (I) any of its enantiomers or any mixture thereof, isotopes thereof or a pharmaceutically acceptable salt thereof, wherein n is 1, 2 or 3; m is 0, 1 or 2; R represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or aralkyl; and R&lt;1 &gt;represents aminophenyl; nitrophenyl; hydroxyphenyl, alkoxyphenyl; a monocyclic 5 to 6 membered heterocyclic group which may be substituted one or more times with substituents or R&lt;1 &gt;represents a bicyclic heterocyclic group, composed of 5 to 6 membered monocyclic heterocyclic group fused to a benzene ring, and which may be substituted one or more times with substituents. The compounds of the invention are useful as nicotinic ACh receptor ligands.

This application is a continuation of PCT International Application No.PCT/DK98/00465 filed on Oct. 27, 1998, which designated the UnitedStates and on which priority is claimed under 35 U.S.C. 120, the entirecontents of which are hereby incorporated by reference.

The present invention relates to novel heteroaryl diazacycloalkanederivatives which are cholinergic ligands at nicotinic ACh receptors.The compounds of the invention are useful for the treatment ofconditions or disorders or diseases involving the cholinergic system ofthe central or peripheral nervous system, pain, inflammatory diseases,diseases caused by smooth muscle contractions and as assistance in thecessation of chemical substance abuse.

BACKGROUND

The endogenous cholinergic neurotransmitter, acetylcholine, exert itsbiological effect via two types of cholinergic receptors; the muscarinicACh receptors and the nicotinic ACh receptors. As it is well establishedthat muscarinic ACh receptors dominate quantitatively over nicotinic AChreceptors in the brain area important to memory and cognition, muchresearch aimed at the development of agents for the treatment of memoryrelated disorders have focused on the synthesis of muscarinic AChreceptor modulators. Recently, however, an interest in the developmentof nicotinic ACh receptor modulators has emerged. Several diseases areassociated with degeneration of the cholinergic system i.e. seniledementia of the Alzheimer type, vascular dementia and cognitiveimpairment due to the organic brain damage disease related directly toalcoholism. Indeed several CNS disorders can be attributed to acholinergic deficiency, a dopaminergic deficiency, an adrenergicdeficiency or a serotonergic deficiency. Alzheimer's disease ischaracterised by a profound loss of memory and cognitive functionscaused by a severe depletion of cholinergic neurons, i.e. neurons thatrelease acetylcholine. A reduction in the number of nicotinic AChreceptors are also observed with the progression of Alzheimer's disease.It is believed that the neurons in the cortex that die with theprogression of Alzheimer's disease do so because of lack of stimulationof the nicotinic ACh receptors. It is predicted that treatment ofAlzheimer's patients with nicotinic ACh receptor modulators will notonly improve the memory of patients but in addition act to keep theseneurons alive. Smoking actually seems to protect individuals againstneurodegeneration and compounds behaving on these receptor may verylikely have a generally neuroprotective effect. However degeneration ofthe cholinergic system is not limited to individuals suffering from i.e.Alzheimers disease but is also seen in healthy aged adults and rats.Therefore it is suggested that the cholinergic system is involved andpartly responsible for the memory disturbances seen in aged animals andhumans. Nicotine receptor modulator may therefore be useful in thetreatment of Alzheimer's disease, memory loss, memory dysfunction,AIDS-dementia, senile dementia or neurodegenerative disorders.Parkinsons disease appears to involve degeneration of dopaminergicneurons. One symptom of the disease has been observed to be loss ofnicotinic receptors associated with the dopaminergic neurons andpossibly interfering with the process of release of dopamine. Assustained nicotine administration increases the number of receptorspresent, administration of nicotine receptor modulators may amelioratethe symptoms of Parkinson's disease. Other condition or disorders ordisease ascribed to deficiencies in the dopaminergic system is: drugaddiction, depression, obesity and narcolepsy. Tourette's syndrome is aneuropsychiatric disorder involving a range of neurological andbehavioral symptoms. It is believed that neurotransmitter dysfunction isinvolved though the pathophysiology is still unknown and that nicotinewill be beneficial in the treatment of the disease (Devor et. al. TheLancet, vol. 8670 p. 1046, 1989) Schizophrenia is a severe psychiatricillness. Neuroleptic compounds has been used in the treatment of thedisease, the effect of the compounds is believed to be interaction inthe dopaminergic system. Nicotine is proposed to be effective in thetreatment of schizophrenia (ie. Adler et. al. Biol. Psychiatry, Vol. 32,p. 607-616, 1992.) Nicotine has been reported to have en effect onneurotransmitter release in several systems. Release of acetylcholineand dopamine by neurons upon administration of nicotine has beenreported (J. Neurochem. vol. 43, 1593-1598, 1984) and release ofnorepinephrine by Hall et. al. (Biochem. Pharmacol. vol. 21, 1829-1838,1972) Release of serotonin by Hery et. al. (Arch. Int. Pharmacodyn.Ther. vol. 296. p. 91-97, 1977). Release of glutamate by Toth et. al(Neurochem. Res. vol. 17, p. 265-271, 1992) The serotonin system anddysfunction's of the serotonergic system is believed to be involved indiseases or conditions or disorders like: anxiety, depression, eatingdisorders, obsessive compulsive disorder, panic disorders, chemicalsubstance abuse, alcoholism, pain, memory deficits and anxiety,pseudodementia, Ganser's syndrome, migraine pain, bulimia, obesity,pre-menstrual syndrome or late luteal phase syndrome, tobacco abuse,post-traumatic syndrome, social phobia, chronic fatigue syndrome,premature ejaculation, erectile difficulty, anorexia nervosa, disordersof sleep, autism, mutism or trichotillomania. Nicotine improvesconcentration and task performance. Therefore compounds exhibitingnicotine receptor modulating properties will be likely to be usefulcompounds in the treatment of learning deficit, cognition deficit,attention deficit, attention deficit hyperactivity disorder anddyslexia. Tobacco use and especially cigarette smoking is recognised asa serious health problem. However nicotine withdrawal symptomsassociated with smoking cessation makes it difficult to break thishabit. Withdrawal symptoms include anger, anxiety, difficulties inconcentrating, restlessness, decreased heart rate and increased appetiteand weight gain. Nicotine itself has shown to ease the withdrawalsymptoms.

Withdrawal from addictive substances, i.e. opiates, benzodiazepines,ethanol, tobacco or nicotine, is in general a traumatic experiencecharacterised by anxiety and frustration. Nicotine has been found to beeffective in reducing anger, irritability, frustration and feelings oftension without causing general response depression, drowsiness orsedation and compounds having same characteristics as nicotine is likelyto have same effects.

Mild to moderate pain is normally treatable with NSAID's (non-steroidalanti-inflammatory drugs) while opiates are used preferentially formoderate to severe pain. The opiates have some well-known side-effects,including chemical dependence and abuse potential as well as adepressive effect on the respiratory and gastrointestinal system. Thereexists therefore a strong need for analgesic compounds that do notexhibit these side effects and which can relieve mild, moderate andsevere pain of acute, chronic or recurrent character as well as migrainepain and postoperative pain, phantom limb pain. Epibatidine, a compoundisolated from the skin of a poison frog, is a very potent analgesic withan approximate potency of 500 times that of morphine. The analgesiceffect is not affected by naloxone, which is an indication of anegligible affinity for the opiate receptors. Epibatidine is annicotinic cholinergic receptor agonist and it is therefore very likely,that compounds possessing this receptor modulating character will alsoshow a strong analgesic response. The compounds of the present inventionhas proven useful for modulation of smooth muscle contractions and maytherefore be used in the treatment or prevention of condition ordisorders or diseases inherent from smooth muscle contractions like i.e.convulsive disorders, angina pectoris, premature labor, convulsions,diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia.

Further, it is well known that nicotine has an effect on appetite and itis predicted that modulators at the nicotine ACh receptor may be usefulas appetite suppressants in the treatment of obesity and eatingdisorders. The cholinergic receptors play an important role in thefunctioning of muscles, organs and generally in the central orperipheral system. There are also complex interactions betweencholinergic receptors and the function of receptors of otherneurotransmitters such as dopamine, serotonin and noradrenaline.

It is likely that nicotine receptor modulator compounds can be effectivein preventing or treating conditions or disorders or diseases like:inflammation, inflammatory skin conditions, Chron's disease,inflammatory bowel disease, irritable colon, ulcerative collitis,irritable colon, diarrhoea, neurodegeneration, perpherical neuropathy,amyotrophic lateral sclerosis, nociception, endocrine disorders,thyrotoxicosis, pheochromocytoma, hypertension, arrhytmias, mania, manicdepression, Huntington's disease, jetlag.

The compounds of the present invention are nicotine receptor modulatorsand has the potential to exhibit nicotinic pharmacology, preferentiallywithout the side effects associated with nicotine itself. Additionally,the compounds are expected to have the potential as enhancers ofneurotransmitter secretion and suppress symptoms associated with a lowactivity of neurotransmitters.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide novel heteroaryldiazacycloalkane derivatives which are useful for the treatment of arange of diseases and disorders characterized by decreased cholinergicfunction or responsive to the activity of nicotinic ACh receptoragonists.

Another object of the present invention is to provide novelpharmaceutical compositions containing these compounds, as well asmethods for the preparation thereof and methods for the treatmenttherewith.

It is yet another object of the invention to provide novel compoundsthat have some if not all of the following favourable characteristics:

A selective binding to the receptor subtypes of neuronal nAChR's, e.g.the non-α7 subtypes.

A low affinity for the muscular subtype.

A oral efficacy in an in vivo (rat model) of arousal/attention.

A low toxicity in vivo.

No adverse effects on heart rate or blood pressure in vivo.

Compounds that are non-mutagenic.

Other objects will become apparent hereinafter to one skilled in theart.

SUMMARY OF THE INVENTION

The invention then, inter alia, comprises the following, alone or incombination:

A compound represented by the general formula

any of its enantiomers or any mixture thereof, isotopes thereof or apharmaceutically acceptable salt thereof;

wherein

n is 1, 2 or 3;

m is 0, 1 or 2;

R represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, or aralkyl;and

R¹ represents aminophenyl; nitrophenyl; hydroxyphenyl, alkoxyphenyl;

a monocyclic 5 to 6 membered heterocyclic group which may be substitutedone or more times with substituents selected from the group consistingof alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy,cycloalkoxy, alkenoxy, alkynoxy, alkynoxy, methylenedioxy, halogen, CF₃,OCF₃, CN, amino, nitro, —COOR³, —CONR²R³, —NH—CO₂R², NHCO—R²,—OCO—NR²R³;

wherein R² and R³ independently represents hydrogen or alkyl;

aryl optionally substituted one or more times with alkyl, cycloalkyl,cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, alkenoxy,alkynoxy, methylenedioxy, halogen, CF₃, OCF₃, CN, amino and nitro;

X-alkyl-Y-alkyl wherein X and Y independently represents O, S, NH,N-alkyl or Se; and alkyl is optionally substituted with alkoxy orthioalkoxy;

X-(alkyl)_(o)-aryl wherein o is 0 or 1 and X represents O, S, NH,N-alkyl or Se; optionally substituted one or more times with alkyl,cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy,alkenoxy, alkynoxy, methylenedioxy, halogen, CF₃, OCF₃, CN, amino andnitro;

X-(alkyl)_(o)-Z wherein o is 0 or 1 and X represents O, S, NH, N-alkylor Se and Z represents a 5- or 6-membered monocyclic heterocyclic group;optionally substituted one or more times with alkyl, cycloalkyl,cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, alkenoxy,alkynoxy, methylenedioxy, halogen, CF₃, OCF₃, CN, amino and nitro;

a monocyclic 5 to 6 membered heterocyclic group optionally substitutedone or more times with alkyl, cycloalkyl, cycloalkylalkyl, alkenyl,alkynyl, alkoxy, cycloalkoxy, alkenoxy, alkynoxy, methylenedioxy,halogen, CF₃, OCF₃, CN, amino and nitro;

or R¹ represents a bicyclic heterocyclic group, composed of a 5 to 6membered monocyclic heterocyclic group fused to a benzene ring, andwhich may be substituted one or more times with substituents selectedfrom the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl,alkynyl, alkoxy, alkoxy-alkoxy, cycloalkoxy, alkenoxy, alkynoxy,methylenedioxy, halogen, CF₃, OCF₃, CN, amino, nitro, aryl optionallysubstituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, alkenoxy, alkynoxy,methylenedioxy, halogen, CF₃, OCF₃, CN, amino and nitro; and amonocyclic 5 to 6 membered heterocyclic group optionally substituted oneor more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl,alkoxy, cycloalkoxy, alkenoxy, alkynoxy, methylenedioxy, halogen, CF₃,OCF₃, CN, amino and nitro;

with the proviso that when R¹ is hydroxyphenyl, alkoxyphenyl,nitrophenyl or aminophenyl, then m and n are not both 2;

A pharmaceutical composition, comprising a therapeutically effectiveamount of a compound of above, or a pharmaceutically acceptable additionsalt thereof, together with at least one pharmaceutically acceptablecarrier or diluent.

The use of a compound as above for the manufacture of a medicament forthe treatment of a disease of a living animal body, including a human,which disease is responsive to the activity of nicotinic ACh receptormodulators.

A compound as above for use as a medicament for treatment of a diseaseof a living animal body, including a human, which disease is responsiveto the activity of nicotinic Ach receptors modulators;

A method of treating a disease of a living animal body, including ahuman, which disease is responsive to the activity of nicotinic AChreceptor modulators, comprising the step of administering to such aliving animal body, including a human, in need thereof a therapeuticallyeffective amount of a compound as above;

DETAILED DISCLOSURE OF THE INVENTION

A preferred aspect of the invention comprises a compound of formula (I)as above wherein the group bridging R and R¹ is a piperazine, ahomopiperazine, a 1,4-di-azacyclooctane, a 1,5-diazacyclooctane, a1,3-diazacyclohexane or an imidazolidine;

Another preferred aspect of the invention comprises compounds of formula(I) as above wherein R is as defined above and R¹ represents anoptionally substituted heteroaryl attached to a piperazine, ahomopiperazine, a 1,4-diazacyclooctane, a 1,5-diazacyclooctane, animidazolidine or a 1,3-diazacyclohexane;

Another preferred aspect of the invention comprises compound of formula(I), as above wherein R¹ represents isoquinolinyl; or phenyl optionallysubstituted with nitro, hydroxy, amino or alkoxy; or pyridyl,quinolinyl, pyridazinyl or pyridinyl all of which may be optionallysubstituted one or more times with alkoxy, cycloalkoxy, alkoxyalkoxy,alkoxycycloalkyl, hydroxyalkoxy, thioalkoxy, thioalkylaryl, alkenoxy,alkynoxy, carboxylamido, a bicyclic heterocyclic group, thioalkoxyaryl,thioaryl, hydroxy or trifluoromethanesulfonyloxy; halogen, phenyloptionally substituted with nitro; a monocyclic 5 to 6 memberedheterocyclic group optionally substituted with alkyl;

Yet another aspect of the invention comprises a compound of formula (I)as above, wherein R¹ represents 3-pyridyl, 3-quinolinyl,5-methoxy-3-pyridyl, 5-chloro-3-pyridyl,5-(4-methyl-1-piperazinyl)-3-pyridyl, 5-ethoxy-3-pyridyl,6-methoxy-3-pyridyl, 5-propyloxy-3-pyridinyl, 5-phenyl-3-pyridyl,5-(2-methyl-propyloxy)-3-pyridyl, 5-propyl-1-en-oxy-3-pyridyl,2-chloro-5-methoxy-3-pyridyl, 6-chloro-5-methoxy-3-pyridyl,6-bromo-5-ethoxy-3-pyridyl, 6-(N-pyrrolidinyl)-3-pyridyl,6-phenyl-3-pyridyl, 5-(3-nitrophenyl)-3-pyridyl, 5-butoxy-3-pyridyl,5-methoxyethoxy-3-pyridyl, 5-(2-methyl-propoxy)-3-pyridyl,5-(2-hydroxy-ethoxy)-3-pyridyl, 5-(3-methyl-butoxy)-3-pyridyl,5-cyclopropylmethoxy-3-pyridyl, 5-propyloxy-3-pyridyl,5-hexyloxy-3-pyridyl, 5-cyclohexylmethoxy-3-pyridyl,6-thioethoxy-3-pyridyl, 5-(2-ethoxy-ethoxy)-3-pyridyl,5-pentyloxy-3-pyridyl, 5-heptyloxy-3-pyridyl,5-(propyl-1-en-oxy)-3-pyridyl, 5-thiobenzyl-3-pyridyl,5-carboxylamido-3-pyridyl, 5-thiophenyl-3-pyridyl,5-methoxy-methoxy)-3-pyridyl, 5-(3-pyridyl)-3-pyridyl,5-(1-pyrrolyl)-3-pyridyl, 5-(1-indolyl)-3-pyridyl,5,6-dimethoxy-3-pyridyl, 5-ethenyloxy-3-pyridyl,5-cyclopentyloxy-3-pyridyl, 5-(ethoxy-d5)-3-pyridyl, 3-chloro-5-pyridyl,3-bromo-5-pyridyl, 4-isoquinolinyl, 5-hydroxy-3-pyridyl,5-trifluoromethanesulfonyl-oxy-3-pyridyl, 5-ethynyl-3-pyridyl,3-nitrophenyl, 3-aminophenyl, 3-methoxyphenyl, 3-hydroxyphenyl,6-chloro-3-pyridazinyl, 6-phenyl-3-pyridazinyl, 6-chloro-2-pyrazinyl,3,6-dimethyl-2-pyrazinyl, 6-methyl-3-pyridazinyl,5-triflouromethyl-3-pyridyl, 6-bromo-3-pyridyl, 6-chloro-3-pyridyl or3-pyridazinyl;

A preferred aspect of the invention comprises a compound of formula (I)as above wherein R represents hydrogen, lower alkyl or aralkyl;

The most preferred aspect of the invention comprises a compound offormula (I), as above, said compound being:

4-Methyl-1-(3-pyridyl)-piperazine;

4-Methyl-1-(3-pyridyl)-piperazine;

4-Methyl-1-(5-methoxy-3-pyridyl)-piperazine;

3,5-Bis-[4,4′-methyl-1,1′-piperazinyl]pyridine;

1-(5-Chloro-3-pyridyl)-4-Methyl-piperazine;

4-Methyl-1-(5-phenyl-3-pyridyl)-piperazine;

1-(5-Ethoxy-3-pyridyl)-4-methyl-piperazine;

1-(5-Butoxy-3-pyridyl)-4-methyl-piperazine;

4-Methyl-1-[5-(propyl-1-en-oxy)-3-pyridyl]-piperazine;

1-(5-Ethenyloxy-3-pyridyl)-4-methyl-piperazine;

1-(5-Methoxy-3-pyridyl)-4-methyl-1,5-diazacyclooctane;

1-(6-Chloro-3-pyridazinyl)-4-methyl-1,5-diazacyclooctane;

1-(3-Pyridyl)-piperazine;

1-(3-Pyridyl)-piperazine;

1-(5-Methoxy-3-pyridyl)-piperazine;

1-(5-Chloro-3-pyridyl)-piperazine;

1-(5-Phenyl-3-pyridyl)-piperazine;

1-(5-Methoxy-3-pyridyl)-1,5-diazacyclooctane;

1-(6-Chloro-3-pyridazinyl)-1,5-diazacyclooctane;

1-(6-Chloro-3-pyridazinyl)-1,4-diazacyclooctane;

1-(5-Ethoxy-3-pyridyl)piperazine;

1-(5-Butoxy-3-pyridyl)piperazine;

1-[5-(Propyl-1-en-oxy)-3-pyridyl]-piperazine;

1-(5-Ethenyloxy-3-pyridyl)piperazine;

1-(5-Ethoxy-3-pyridyl)-1,5-diazacyclooctane,

1-(5-Propyloxy-3-pyridinyl)-1,5-diazacyclooctane,

1-[5-(Propyl-1-en-oxy)-3-pyridyl]-1,5-diazacyclooctane,

1-(5-Ethenyloxy-3-pyridyl) 1,5-diazacyclooctane;

1-(5-Ethoxy-3-pyridyl)-4-ethyl-piperazine;

4-Methyl-1-(3-pyridyl)-homopiperazine;

4-Methyl-1-(3-pyridyl)-homopiperazine;

1-(5-Methoxy-3-pyridyl)-4-methyl-homopiperazine;

1-(5-Ethoxy-3-pyridyl)-4-methyl-homopiperazine;

4-Methyl-1-(5-phenyl-3-pyridyl)-homopiperazine;

1-(5-Butoxy-3-pyridyl)-4-methyl-homopiperazine;

1-(5-Methoxyethoxy-3-pyridyl)-4-methyl-homopiperazine;

4-Methyl-1-[5-(2-methyl-propyloxy)-3-pyridyl]-homopiperazine;

1-(5-Cyclopropylmethoxy-3-pyridyl)-4-methyl-homopiperazine;

4-Methyl-1-(5-propyloxy-3-pyridyl)-homopiperazine;

1-(5-Hexyloxy-3-pyridyl)-4-methyl-homopiperazine;

4-Methyl-1-[5-(3-methyl-butoxy)-3-pyridyl]-homopiperazine;

4-Methyl-1-(6-thioethoxy-3-pyridyl)-homopiperazine;

1-(5-Cyclohexylmethoxy-3-pyridyl)-4-methyl-homopiperazine;

4-Methyl-1-(5-pentyloxy-3-pyridyl)-homopiperazine;

1-(5-Heptyloxy-3-pyridyl)-4-methyl-homopiperazine;

4-Methyl-1-(5-propyl-1-en-oxy-3-pyridyl)-homopiperazine;

4-Methyl-1-(5-thiobenzyl-3-pyridyl)-homopiperazine;

4-Methyl-1-[5-(3-pyridyl)-3-pyridyl]-homopiperazine;

4-Methyl-1-(3-nitrophenyl)-homopiperazine;

4-Methyl-1-(6-chloro-3-pyridazinyl)-homopiperazine;

4-Methyl-1-(6-phenyl-3-pyridazinyl)-homopiperazine;

4-Methyl-1-(3-pyridazinyl)-homopiperazine;

4-Methyl-1-(6-methyl-3-pyridazinyl)-homopiperazine;

1-(5-Cyclopentyloxy-3-pyridyl)-4-methyl-homopiperazine;

4-Benzyl-1-(3-pyridyl)-homopiperazine;

4-Ethyl-1-(3-pyridyl)-homopiperazine;

1-(3-Pyridyl)-homopiperazine;

1-(3-Pyridyl)-homopiperazine;

1-(6-Methoxy-3-pyridyl)-homopiperazine;

1-(2-Chloro-5-methoxy-3-pyridyl)-homopiperazine;

1-(6-Chloro-5-methoxy-3-pyridyl)-homopiperazine;

1-(6-Bromo-5-ethoxy-3-pyridyl)-homopiperazine;

1-[6-(N-Pyrrolidinyl)-3-pyridyl]-homopiperazine;

1-(6-Phenyl-3-pyridyl)-4-homopiperazine;

1-[5-(3-Nitrophenyl)-3-pyridyl]-4-homopiperazine;

1-(5-Methoxy-3-pyridyl)-homopiperazine;

1-(5-Phenyl-3-pyridyl)-homopiperazine;

1-(5-Ethoxy-3-pyridyl)-homopiperazine;

1-(5-Butoxy-3-pyridyl)-homopiperazine;

1-(5-Methoxyethoxy-3-pyridyl)-homopiperazine;

1-[5-(2-Methyl-propoxy)-3-pyridyl]-homopiperazine;

1-[5-(2-Hydroxy-ethoxy)-3-pyridyl]-homopiperazine;

1-[5-(3-Methyl-butoxy)-3-pyridyl]-homopiperazine;

1-(5-Cyclopropylmethoxy-3-pyridyl)-homopiperazine;

1-(5-Propyloxy-3-pyridyl)-homopiperazine;

1-(5-Hexyloxy-3-pyridyl)-homopiperazine;

1-(5-Cyclohexylmethoxy-3-pyridyl)-homopiperazine;

1-(6-Thioethoxy-3-pyridyl)-homopiperazine;

1-[5-(2-Ethoxy-ethoxy)-3-pyridyl]-homopiperazine;

1-(5-Pentyloxy-3-pyridyl)-homopiperazine;

1-(5-Heptyloxy-3-pyridyl)-homopiperazine;

1-[5-(Propyl-1-en-oxy)-3-pyridyl]-homopiperazine;

1-(5-Thiobenzyl-3-pyridyl)-homopiperazine;

1-(5-Carboxylamido-3-pyridyl)-homopiperazine;

1-(5-Thiophenyl-3-pyridyl)-homopiperazine;

1-[(5-Methoxy-methoxy)-3-pyridyl]-homopiperazine;

1-[5-(3-Pyridyl)-3-pyridyl]-homopiperazine;

1-(5-(1-Pyrrolyl)-3-pyridyl)-homopiperazine;

1-(5-(1-Indolyl)-3-pyridyl)-homopiperazine;

1-(5,6-Dimethoxy-3-pyridyl)-homopiperazine;

1-(5-Ethenyloxy-3-pyridyl)homopiperazine;

1-(5-Cyclopentyloxy-3-pyridyl)homopiperazine;

1-[5-(Ethoxy-d5)-3-pyridyl]-homopiperazine;

1-(3-Chloro-5-pyridyl)homopiperazine;

1-(3-Bromo-5-pyridyl)homopiperazine;

1-(4-Isoquinolinyl)-homopiperazine;

1-(5-Hydroxy-3-pyridyl)-homopiperazine;

1-(5-Trifluoromethanesulfonyl-oxy-3-pyridyl)-homopiperazine;

1-(5-Ethynyl-3-pyridyl)-homopiperazine;

1-(3-Nitrophenyl)-homopiperazine;

1-(3-Aminophenyl)-homopiperazine;

1-(3-Methoxyphenyl)-homopiperazine;

1-(3-Hydroxyphenyl)-homopiperazine;

1-(6-Chloro-3-pyridazinyl)-homopiperazine;

1-(6-Phenyl-3-pyridazinyl)-homopiperazine;

1-(6-Chloro-2-pyrazinyl)-homopiperazine;

1-(3,6-Dimethyl-2-pyrazinyl)-homopiperazine;

1-(6-Methyl-3-pyridazinyl)-homopiperazine;

1-(5-Triflouromethyl-3-pyridyl)-homopiperazine;

1-(6-Bromo-3-pyridyl)-homopiperazine;

1-(6-Chloro-3-pyridyl)-homopiperazine;

1-(3-Pyridazinyl)-homopiperazine;

N-(5-Methoxy-3-pyridyl)-ethylenediamine;

1-(5-Methoxy-3-pyridyl)-imidazolidine;

1-(5-Methoxy-3-pyridyl)-1,3-diazacyclohexane;

1-(5-Benzyloxy-3-pyridyl)-piperazine;

1-(5-Benzyloxy-3-pyridyl)-homopiperazine;

4-Methyl-1-(5-benzyloxy-3-pyridyl)-piperazine;

4-Methyl-1-(5-benzyloxy-3-pyridyl)-homopiperazine;

1-(5-Thiobenzyloxy-3-pyridyl)-piperazine;

4-Methyl-1-(5-thiobenzyloxy-3-pyridyl)-piperazine;

1-(5-Phenoxy-3-pyridyl)-piperazine;

1-(5-Phenoxy-3-pyridyl)-homopiperazine;

4-Methyl-1-(5-phenoxy-3-pyridyl)-piperazine;

4-Methyl-1-(5-phenoxy-3-pyridyl)-homopiperazine;

1-(5-Thiophenoxy-3-pyridyl)-piperazine;

4-Methyl-1-(5-thiophenoxy-3-pyridyl)-piperazine;

4-Methyl-1-(5-thiophenoxy-3-pyridyl)-homopiperazine;

1-(5-(3-Pyridyloxy)-3-pyridyl)-piperazine;

1-(5-(3-Pyridyloxy)-3-pyridyl)-homopiperazine;

4-Methyl-1-(5-(3-pyridyloxy)-3-pyridyl)-piperazine;

4-Methyl-1-(5-(3-pyridyloxy)-3-pyridyl)-homopiperazine;

1-(5-(2-Thiopyridyloxy)-3-pyridyl)-piperazine;

1-(5-(2-Thiopyridyloxy)-3-pyridyl)-homopiperazine;

4-Methyl-1-(5-(2-thiopyridyloxy)-3-pyridyl)-piperazine;

4-Methyl-1-(5-(2-thiopyridyloxy)-3-pyridyl)-homopiperazine;

1-(5-(4-Thiopyridyloxy)-3-pyidyl)-piperazine;

1-(5-(4-Thiopyridyloxy)-3-pyridyl)-homopiperazine;

4-Methyl-1-(5-(4-thiopyridyloxy)-3-pyridyl)-piperazine;

4-Methyl-1-(5-(4-thiopyridyloxy)-3-pyridyl)-homopiperazine;

1-(5-(2-Pyridyl)-3-pyridyl)-piperazine;

1-(5-(3-Pyridyl)-3-pyridyl)-piperazine;

1-(5-(4-Pyridyl)-3-pyridyl)-piperazine;

1-(5-(2-Pyridyl)-3-pyridyl)-homopiperazine;

1-(5-(4-Pyridyl)-3-pyridyl)-homopiperazine;

4-Methyl-1-(5-(2-pyridyl)-3-pyridyl)-piperazine;

4-Methyl-1-(5-(3-pyridyl)-3-pyridyl)-piperazine;

4-Methyl-1-(5-(4-pyridyl)-3-pyridyl)-piperazine;

4-Methyl-1-(5-(2-pyridyl)-3-pyridyl)-homopiperazine;

4-Methyl-1-(5-(4-pyridyl)-3-pyridyl)-homopiperazine;

1-(5-(2-Furanyl)-3-pyridyl)piperazine;

4-Methyl-1-(5-(2-furanyl)-3-pyridyl)piperazine;

1-(5-(3-Furanyl)-3-pyridyl)piperazine;

4-Methyl-1-(5-(3-furanyl)-3-pyridyl)piperazine;

1-(5-(2-Thienyl)-3-pyridyl)piperazine;

1-(5-(2-Thienyl)-3-pyridyl)homopiperazine;

4-Methyl-1-(5-(2-thienyl)-3-pyridyl)piperazine;

4-Methyl-1-(5-(2-thienyl)-3-pyridyl)homopiperazine;

1-(5-(3-Thienyl)-3-pyridyl)piperazine;

1-(5-(3-Thienyl)-3-pyridyl)homopiperazine;

4-Methyl-1-(5-(3-thienyl)-3-pyridyl)piperazine;

4-Methyl-1-(5-(3-thienyl)-3-pyridyl)homopiperazine;

1-(5-(2-Thiazolyl)-3-pyridyl)piperazine;

1-(5-(2-Thiazolyl)-3-pyridyl)homopiperazine;

4-Methyl-1-(5-(2-thiazolyl)-3-pyridyl)piperazine;

4-Methyl-1-(5-(2-thiazolyl)-3-pyridyl)homopiperazine;

1-(5-(Methyl-ethylendioxy)-3-pyridyl)piperazine;

4-Methyl-1-(5-(methyl-ethylendioxy)-3-pyridyl)piperazine;

1-(5-(Ethyl-ethylendioxy)-3-pyridyl)piperazine;

4-Methyl-1-(5-(ethyl-ethylendioxy)-3-pyridyl)piperazine;

1-(5-(Butyl-ethylendioxy)-3-pyridyl)piperazine;

1-(5-(Butyl-ethylendioxy)-3-pyridyl)homopiperazine;

4-Methyl-1-(5-(butyl-ethylendioxy)-3-pyridyl)piperazine;

4-Methyl-1-(5-(butyl-ethylendioxy)-3-pyridyl)homopiperazine;

1-(5-(Propyl-ethylendioxy)-3-pyridyl)piperazine;

1-(5-(Propyl-ethylendioxy)-3-pyridyl)homopiperazine;

4-Methyl-1-(5-(propyl-ethylendioxy)-3-pyridyl)piperazine;

4-Methyl-1-(5-(propyl-ethylendioxy)-3-pyridyl)homopiperazine;

1-(5-(1,4,7-Toxanonyl)-3-pyridyl)piperazine;

1-(5-(1,4,7-Trioxanonyl)-3-pyridyl)homopiperazine;

4-Methyl-1-(5-(1,4,7-trioxanonyl)-3-pyridyl)piperazine;

4-Methyl-1-(5-(1,4,7-trioxanonyl)-3-pyridyl)homopiperazine;

1-(5-(1,7-Dioxa-4-thia-octanyl)-3-pyridyl)piperazine;

1-(5-(1,7-Dioxa-4-thia-octanyl)-3-pyridyl)homopiperazine;

4-Methyl-1-(5-(1,7-dioxa-4-thia-octanyl)-3-pyridyl)piperazine;

4-Methyl-1-(5-(1,7-dioxa-4-thia-octanyl)-3-pyridyl)homopiperazine;

1-(5-(2-Methylthio-ethoxy)-3-pyridyl)piperazine;

1-(5-(2-Methylthio-ethoxy)-3-pyridyl)homopiperazine;

4-Methyl-1-(5-(2-methylthio-ethoxy)-3-pyridyl)piperazine;

4-Methyl-1-(5-(2-methylthio-ethoxy)-3-pyridyl)homopiperazine;

1-(5-(2-Ethylthio-ethoxy)-3-pyridyl)piperazine;

1-(5-(2-Ethylthio-ethoxy)-3-pyridyl)homopiperazine;

4-Methyl-1-(5-(2-ethylthio-ethoxy)-3-pyridyl)piperazine;

4-Methyl-1-(5-(2-ethylthio-ethoxy)-3-pyridyl)homopiperazine;

1-(5-(Cyclopropylmethoxy)-3-pyridyl)piperazine;

4-Methyl-1-(5-(cyclopropylmethoxy)-3-pyridyl)piperazine;

1-(5-(sec-Butoxy)-3-pyridyl)piperazine;

4-Methyl-1-(5-(sec-butoxy)-3-pyridyl)piperazine;

1-(5-(Isopentoxy)-3-pyridyl)piperazine;

4-Methyl-1-(5-(isopentoxy)-3-pyridyl)piperazine;

1-(5-(Isopropoxy)-3-pyridyl)piperazine;

1-(5-(Isopropoxy)-3-pyridyl)homopiperazine;

4-Methyl-1-(5-(isopropoxy)-3-pyridyl)piperazine;

4-Methyl-1-(3-pyridyl)-1,4-diazacyclooctane;

1-(3-Pyridyl)-1,4-diazacyclooctane;

1-(3-Pyridyl)-1,5-diazacyclooctane

4-Methyl-1-(3-pyridyl)-1,5-diazacyclooctane;

or a pharmaceutically acceptable addition salt thereof;

Pharmaceutical Acceptable Addition Salts

The chemical compound of the invention may be provided in any formsuitable for the intended administration. Suitable forms includepharmaceutically (i.e. physiologically) acceptable salts, and pre- orprodrug forms of the chemical compound of the invention. Examples ofpharmaceutically acceptable addition salts include, without limitation,the non-toxic inorganic and organic acid addition salts such as theacetate derived from acetic acid, the aconate derived from aconiticacid, the ascorbate derived from ascorbic acid, the benzenesulfonatederived from benzensulfonic acid, the benzoate derived from benzoicacid, the cinnamate derived from cinnamic acid, the citrate derived fromcitric acid, the embonate derived from embonic acid, the enantatederived from enanthic acid, the formate derived from formic acid, thefumarate derived from fumaric acid, the glutamate derived from glutamicacid, the glycolate derived from glycolic acid, the hydrochloridederived from hydrochloric acid, the hydrobromide derived fromhydrobromic acid, the lactate derived from lactic acid, the maleatederived from maleic acid, the malonate derived from malonic acid, themandelate derived from mandelic acid, the methanesulfonate derived frommethane sulphonic acid, the naphthalene-2-sulphonate derived fromnaphtalene-2-sulphonic acid, the nitrate derived from nitric acid, theperchlorate derived from perchloric acid, the phosphate derived fromphosphoric acid, the phthalate derived from phthalic acid, thesalicylate derived from salicylic acid, the sorbate derived from sorbicacid, the stearate derived from stearic acid, the succinate derived fromsuccinic acid, the sulphate derived from sulphuric acid, the tartratederived from tartaric acid, the toluene-p-sulphonate derived fromp-toluene sulfonic acid, and the like. Such salts may be formed byprocedures well known and described in the art. Other acids such asoxalic acid, which may not be considered pharmaceutically acceptable,may be useful in the preparation of salts useful as intermediates inobtaining a chemical compound of the invention and its pharmaceuticallyacceptable acid addition salt. Metal salts of a chemical compound of theinvention includes alkali metal salts, such as the sodium salt of achemical compound of the invention containing a carboxy group. Thechemical compound of the invention may be provided in solved or unsolvedform together with a pharmaceutically acceptable solvents such as water,ethanol and the like. In general, solved forms are considered equivalentto dissolved forms for the purposes of this invention.

Steric Isomers

The chemical compounds of the present invention may exist in (+) and (−)forms as well as in racemic forms. The racemates of these isomers andthe individual isomers themselves are within the scope of the presentinvention. Racemic forms can be resolved into the optical antipodes byknown methods and techniques. One way of separating the diastereomericsalts is by use of an optically active acid, and liberating theoptically active amine compound by treatment with a base. Another methodfor resolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of d- or l- (tartrates, mandelates,or camphorsulphonate) salts for example. The chemical compounds of thepresent invention may also be resolved by the formation ofdiastereomeric amides by reaction of the chemical compounds of thepresent invention with an optically active activated carboxylic acidsuch as that derived from (+) or (−) phenylalanine, (+) or (−)phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981). Moreover, some of the chemical compounds of theinvention contains double bonds and may thus exist in two forms, cis-and trans-forms (Z- and E-form), depending on the arrangement of thesubstituents around the —C═C— double bond. A chemical compound of thepresent invention may thus be the cis- or trans-form (Z- and E-form), orit may be a mixture hereof.

Definition of Substituents

Halogen is fluorine, chlorine, bromine or iodine.

Alkyl means a straight chain or branched chain of one to eight carbonatoms, including but not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, and hexyl;

Cycloalkyl means cyclic alkyl of three to seven carbon atoms, includingbut not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

Alkenyl means a group of from two to six carbon atoms, including atleast one double bond, for example, but not limited to ethenyl, 1,2- or2,3-propenyl, 1,2-, 2,3-, or 3,4-butenyl.

Alkynyl means a group of from two to six carbon atoms, including atleast one triple bond, for example, but not limited to ethynyl, 1,2- or2,3-propynyl, 1,2- or 2,3- or 3,4-butynyl.

Cycloalkylalkyl means cycloalkyl as above and alkyl as above, meaningfor example, cyclopropylmethyl.

Alkoxy is O-alkyl, wherein alkyl is as defined above.

Cycloalkoxy is O-cycloalkyl, wherein cycloalkyl is as defined above.

Alkenoxy is O-alkenyl wherein alkenyl is as defined above.

Alkynoxy is O-alkynyl, wherein alkynyl is as defined above;

Thioalkoxy is S-alkyl, wherein alkyl is as defined above.

Amino is NH₂ or NH-alkyl or N-(alkyl)₂, wherein alkyl is as definedabove.

A monocyclic 5- to 6-membered heterocyclic group includes, for example,oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl,isoxazol-5-yl, thiazol-2-yl, thiazol4-yl, thiazol-5-yl, isothiazol-3-yl,isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,4thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl,1,2,5-thiadiazol-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyland 3-pyrazinyl and 1-pyrazolyl, 3-pyrazolyl, and 4-pyrazolyl.

A bicyclic heterocyclic group composed of a 5 to 6 membered monocyclicheterocyclic group and a fused benzene ring means a monocyclic 5 to 6membered heterocyclic group as above which is fused to a benzene ringincluding, for example, 2-, 3-, 4-, 5-, 6-, 7-benzofuranyl, 1-, 2-, 4-,5-benzimidazolyl, 2-, 3-, 4-, 5-, 6-, 7-indolyl,2-,3-,4-,5-,6-,7-,8-quinolinyl and 1-,3-,4-,5-,6-,7-,8-isoquinolinyl.

Aryl is an aromatic hydrocarbon, such as phenyl and naphthyl.

Aralkyl means alkyl as above and aryl as above, meaning for examplebenzyl, phenethyl.

Isotopes means one or more atom in the compound is substituted with anisotope of the naturally occuring atoms and includes though not limitedto deuterium, tritium, ¹³C, ¹⁴C, ¹³¹I, ¹²⁵I, ¹²³I, ¹⁸F;

Further, the compounds of this invention may exist in unsolvated as wellas in solvated forms with pharmaceutically acceptable solvents such aswater, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

It will be appreciated by those skilled in the art that the compounds ofthe present invention may contain several chiral centers and that suchcompounds exist in the form of isomers (i.e. enantiomers). The inventionincludes all such isomers and any mixtures thereof including racemicmixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example, by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. Racemic compounds of the present invention canthus be resolved into their optical antipodes, e.g., by fractionalcrystallization of d- or l-(tartrates, mandelates, or camphorsulphonate)salts for example. The compounds of the present invention may also beresolved by the formation of diastereomeric amides by reaction of thecompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the compounds of the presentinvention with an optically active chloroformate or the like.

Additional methods for the resolvation of optical isomers, known tothose skilled in the art may be used, and will be apparent to theaverage worker skilled in the art. Such methods include those discussedby J. Jaques, A. Collet, and S. Wilen in “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

The compounds of the invention may be prepared by any conventionalmethod useful for the preparation of analogous compounds and asdescribed in the examples below.

Starting materials for the processes described in the present patentapplication are known or can be prepared by known processes fromcommercially available materials

A compound of the invention can be converted to another compound of theinvention using conventional methods.

The products of the reactions described herein are isolated byconventional means such as extraction, crystallization, distillation,chromatography, and the like.

Biology

Nicotinic ACh receptors in the brain are pentameric structures composedof subunits distinct from those found in skeletal muscles. The existenceof seven α-subunits (α2-α7, α9) and three β-subunits (β2-β4) in themammalian brain has been described.

The predominant subtype with high affinity for nicotine is comprised ofα₄ and β₂ subunits.

The affinity of compounds of the invention for nicotinic ACh receptorshave been investigated in three test for in vitro inhibition of³H-epibatidin binding, ³H-α-bungarotoxin binding and ³H-cytisine bindingas described below:

In vitro Inhibition of ³H-cytisine Binding

The predominant subtype with high affinity for nicotine is comprised ofα₄ and β₂ subunits. nAChRs of the latter type can selectively belabelled by the nicotine agonist ³H-cytisine.

Tissue Preparation

Preparations are performed at 0-4° C. unless otherwise indicated.Cerebral corticies from male Wistar rats (150-250 g) are homogenized for20 sec in 15 ml Tris, HCl (50 mM, pH 7.4) containing 120 mM NaCl, 5 mMKCl, 1 mM MgCl₂ and 2.5 mM CaCl₂ using an Ultra-Turrax homogenizer. Thehomogenate is centrifuged at 27,000×g for 10 min. The supernatant isdiscarded and the pellet is resuspended in fresh buffer and centrifugeda second time. The final pellet is resuspended in fresh buffer (35 mlper g of original tissue) and used for binding assays.

Assay

Aliquots of 500 μl homogenate are added to 25 μl of test solution and 25μl of ³H-cytisine (1 nM, final concentration), mixed and incubated for90 min at 2° C. Non-specific binding is determined using (−)-nicotine(100 μM, final concentration). After incubation the samples are added 5ml of ice-cold buffer and poured directly onto Whatman GF/C glass fibrefilters under suction and immediately washed with 2×5 ml ice-coldbuffer. The amount of radioactivity on the filters is determined byconventional liquid scintillation counting. Specific binding is totalbinding minus non-specific binding.

In vitro Inhibition of ³H-α-bungarotoxin Binding Rat Brain

α-Bungarotoxin is a peptide isolated from the venom of the Elapidaesnake Bungarus multicinctus (Mebs et al., Biochem. Biophys. Res.Commun., 44(3), 711 (1971)) and has high affinity for neuronal andneuromuscular nicotinic receptors, where it acts as a potent antagonist.³H-α-Bungarotoxin binds to a single site in rat brain with an uniquedistribution pattern in rat brain (Clarke et al., J. Neurosci. 5,1307-1315 (1985)).

³H-α-Bungarotoxin labels nAChR formed by the α₇ subunit isoform found inbrain and the α₁ isoform in the neuromuscular junction (Changeaux, FidiaRes. Found. Neurosci. Found. Lect. 4, 21-168 (1990). Functionally, theα₇ homo-oligomer expressed in oocytes has a calcium permeability greaterthan neuromuscular receptors and, in some instances greater than NMDAchannels (Seguela et al., J. Neurosci. 13, 596-604 (1993).

Tissue Preparation

Preparations are performed at 0-4° C. unless otherwise indicated.Cerebral cortices from male Wistar rats (150-250 g) are homogenized for10 sec in 15 ml 20 mM Hepes buffer containing 118 mM NaCl, 4.8 mM KCl,1.2 mM MgSO₄ and 2.5 mM CaCl₂ (pH 7.5) using an Ultra-Turraxhomogenizer. The tissue suspension is centrifuged at 27,000×g for 10min. The supernatant is discarded and the pellet is washed twice bycentrifugation at 27,000×g for 10 min in 20 ml fresh buffer, and thefinal pellet is resuspended in fresh buffer containing 0.01% BSA (35 mlper g of original tissue) and used for binding assays.

Assay

Aliquots of 500 μl homogenate are added to 25 μl of test solution and 25μl of ³H-α-bungarotoxin (2 nM, final concentration), mixed and incubatedfor 2 h at 37° C. Non-specific binding is determined using (−)-nicotine(1 mM, final concentration). After incubation the samples are added 5 mlof ice-cold Hepes buffer containing 0.05% PEI and poured directly ontoWhatman GF/C glass fibre filters (presoaked in 0.1% PEI for at least 6h) under suction and immediately washed with 2×5 ml ice-cold buffer. Theamount of radioactivity on the filters is determined by conventionalliquid scintillation counting. Specific binding is total binding minusnon-specific binding.

In vitro Inhibition of ³H-epibatidin Binding

Epibatidin is an alkaloid that was first isolated from the skin of theEcuadoran frog Epipedobates tricolor and was found to have very highaffinity for neuronal nicotinic receptors, where it acts as a potentagonist. ³H-epibatidin binds to two sites in rat brain, both of whichhave pharmacological profiles consistent with neuronal nicotinicreceptors and a similar brain regional distribution (Hougling et al.,Mol. Pharmacol. 48, 280-287 (1995)).

The high affinity binding site for ³H-epibatidin is most certainlybinding to the α₄β₂ subtype of nicotinic receptors. The identity of thelow affinity site is still unknown; does it represent a second nicotinicreceptor or a second site in the same receptor. The inability ofα-bungarotoxin to compete for ³H-epibatidin binding sites indicates thatneither site measured represents the nicotinic receptor composed of α₇subunits.

Tissue Preparation

Preparations are performed at 0-4° C. unless otherwise indicated. Theforebrain (÷cerebellum) from a male Wistar rat (150-250 g) ishomogenized for 10-20 sec in 20 ml Tris, HCl (50 mM, pH 7.4) using anUltra-Turrax homogenizer. The tissue suspension is centrifuged at27,000×g for 10 min. The supernatant is discarded and the pellet iswashed three times by centrifugation at 27,000×g for 10 min in 20 mlfresh buffer, and the final pellet is resuspended in fresh buffer (400ml per g of original tissue) and used for binding assays.

Assay

Aliquots of 2.0 ml homogenate are added to 0.100 ml of test solution and0.100 ml of ³H-epibatidin (0.3 nM, final concentration), mixed andincubated for 60 min at room temperature. Non-specific binding isdetermined using (−)-nicotine (30 μM, final concentration). Afterincubation the samples are poured directly onto Whatman GF/C glass fibrefilters (presoaked in 0.1% PEI for at least 20 min) under suction andimmediately washed with 2×5 ml ice-cold buffer. The amount ofradioactivity on the filters is determined by conventional liquidscintillation counting. Specific binding is total binding minusnon-specific binding.

³H- ³H-α- ³H- epi- bung- cytisine batidin arotoxin IC₅₀ IC₅₀ IC₅₀Compound (μM) (μM) (μM) 4-Methyl-1-(3-pyridyl)-piperazine fumaric 0.060.38 6.80 acid salt (1A) 4-Methyl-1-(5-methoxy-3-pyridyl)- 0.068 0.3832.50 piperazine (3A) 1-(5-Chloro-3-pyridyl)-4-Methyl-piperazine 0.080.65 73.40 fumaric acid salt (5A)4-Methyl-1-(5-phenyl-3-pyridyl)-piperazine 0.08 1.10 >30 fumaric acidsalt (6A) 1-(5-Ethoxy-3-pyridyl)-4-methyl-piperazine 0.006 0.09 >30fumaric acid salt (7A) 1-(5-Methoxy-3-pyridyl)-4-methyl-1,5- 0.041.2 >30 diazacyclooctane fumaric acid salt (11A)1-(3-Pyridyl)-piperazine fumaric acid salt 0.13 0.63 >30 (1B)1-(5-Methoxy-3-pyridyl)-piperazine fumaric 0.80 4.50 >30 acid salt (3B)1-(5-Chloro-3-pyridyl)-piperazine fumaric 0.31 3.00 >30 acid salt (4B)1-(5-Methoxy-3-pyridyl)-1,5- 0.001 0.0032 2.5 diazacyclooctane fumaricacid salt (6B) 1-(6-Chloro-3-pyridazinyl)-1,5- 0.03 0.15 0.46diazacyclooctane fumaric acid salt (7B) 1-(6-Chloro-3-pyridazinyl)-1,4-0.55 0.92 5.50 diazacyclooctane fumaric acid salt (8B)1-(5-Ethoxy-3-pyridyl)piperazine fumaric 0.50 1.00 >30 acid salt (1D)1-(5-Butoxy-3-pyridyl)piperazine fumaric 0.18 1.40 >30 acid salt (2D)1-(5-Ethoxy-3-pyridyl)-4-ethyl-piperazine 0.07 0.21 >30 fumaric acidsalt (9D) 4-Methyl-1-(3-pyridyl)-homopiperazine (1E) 0.15 0.4 4.64-Methyl-1-(3-quinolinyl)-homopiperazine 0.34 4.90 1.80 fumaric acidsalt (2E) 1-(5-Methoxy-3-pyridyl)-4-methyl- 0.094 0.75 26.00homopiperazine fumaric acid salt (3E) 1-(5-Ethoxy-3-pyridyl)-4-methyl-0.05 0.30 >30 homopiperazine fumaric acid salt (4E)4-Methyl-1-(5-phenyl-3-pyridyl)- 0.20 1.50 16.0 homopiperazine fumaricacid salt (5E) 1-(5-Butoxy-3-pyridyl)-4-methyl- 0.045 0.24 >30homopiperazine fumaric acid salt (6E)1-(5-Methoxyethoxy-3-pyridyl)-4-methyl- 0.07 0.55 >30 homopiperazine(7E) 4-Methyl-1-[5-(2-methyl-propyloxy)-3- 0.07 0.45 >30pyridyl]-homopiperazine fumaric acid salt (8E)1-(5-Cyclopropylmethoxy-3-pyridyl)-4- 0.078 4.80 >30methyl-homopiperazine fumaric acid salt (9E)4-Methyl-1-(5-propyloxy-3-pyridyl)- 0.06 0.29 >30 homopiperazine fumaricacid salt (10E) 1-(5-Hexyloxy-3-pyridyl)-4-methyl- 0.80 0.25 >30homopiperazine fumaric acid salt (11E)4-Methyl-1-[5-(3-methyl-butoxy)-3-pyridyl]- 0.055 0.27 >30homopiperazine fumaric acid salt (12E)1-(5-Cyclohexylmethoxy-3-pyridyl)-4- 0.20 0.48 >30 methyl-homopiperazinefumaric acid salt (14E) 4-Methyl-1-(5-pentyloxy-3-pyridyl)- 0.030.21 >30 homopiperazine fumaric acid salt (15E)1-(5-Heptyloxy-3-pyridyl)-4-methyl- 0.28 0.70 >30 homopiperazine fumaricacid salt (16E) trans-4-Methyl-1-(5-propyl-1-en-oxy-3- 0.02 0.09 >30pyridyl)-homopiperazine fumaric acid salt (17E)4-Methyl-1-(5-thiobenzyl-3-pyridyl)- 0.60 0.80 15.0 homopiperazinefumaric acid salt (18E) 4-Methyl-1-[5-(3-pyridyl)-3-pyridyl]- 0.171.80 >30 homopiperazine fumaric acid salt (19E)1-(5-Cyclopentyloxy-3-pyridyl)-4-methyl- 0.08 0.61 >30 homopiperazinefumaric acid salt (25E) 1-(3-Pyridyl)-homopiperazine fumaric acid 0.0020.005 0.19 salt (1F) 1-(3-Quinolinyl)-homopiperazine fumaric 0.006 0.0845.90 acid salt (2F) 1-(6-Chloro-5-methoxy-3-pyridyl)- 0.0007 0.005 0.90homopiperazine fumaric acid salt (5F)1-(5-Methoxy-3-pyridyl)-homopiperazine 0.002 0.02 3.00 fumaric acid salt(1H) 1-(5-Phenyl-3-pyridyl)-homopiperazine 0.003 0.02 37.00 fumaric acidsalt (2H) 1-(5-Ethoxy-3-pyridyl)-homopiperazine 0.002 0.01 20.00 fumaricacid salt (3H) 1-(5-Methoxyethoxy-3-pyridyl)- 0.002 0.02 19.00homopiperazine fumaric acid salt (5H)1-[5-(2-Methyl-propoxy)-3-pyridyl]- 0.002 0.01 >30 homopiperazinefumaric acid salt (6H) 1-(5-Cyclopropylmethoxy-3-pyridyl)- 0.0010.006 >30 homopiperazine fumaric acid salt (9H)1-(5-Propyloxy-3-pyridyl)-homopiperazine 0.0009 0.0054 >30 fumaric acidsalt (10H) 1-(6-Chloro-3-pyridazinyl)-homopiperazine 0.01 0.06 1.40fumaric acid salt (1K) 1-(6-Chloro-2-pyrazinyl)-homopiperazine 0.02 0.165.60 fumaric acid salt (3K) 1-(6-Methyl-3-pyridazinyl)-homopiperazine0.16 0.74 4.80 fumaric acid salt (5K) 1-(5-Triflouromethyl-3-pyridyl)-0.009 0.04 6.40 homopiperazine fumaric acid salt(6K)1-(6-Bromo-3-pyridyl)-homopiperazine 0.001 0.01 0.62 fumaric acid salt(8K) 1-(3-Pyridazinyl)-homopiperazine (1L) 0.03 0.25 1.601-(2-Quinoxalinyl)-homopiperazine fumaric 0.26 2.00 27.00 acid salt (2L)1-(5-Methoxy-3-pyridyl)-3-methyl- 0.59 8.80 >30.0 imidazolidine fumaricacid salt (1M) 1-(5-Methoxy-3-pyridyl)-3-methyl-1.3- 0.09 2.70 >30diazacyclohexane fumaric acid salt (2M)

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers therefor and, optionally, other therapeutic and/orprophylactic ingredients. The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, or capsules filled with thesame, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. Formulations containingten (10) milligrams of active ingredient or, more broadly, 0.1 to onehundred (100) milligrams, per tablet, are accordingly suitablerepresentative unit dosage forms.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavoured base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multidose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, formulations adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

Method of Treating

The compounds of the present invention are valuable nicotinic AChreceptor modulators and therefore useful for the treatment of a range ofailments involving cholinergic dysfunction as well as a range ofdisorders responsive to the activity of nicotinic ACh receptormodulators. The compounds may be used in the treatment, prevention,profylaxis or alleviation of a disease, disorder or condition of thecentral or peripheral system as for example: neurodegenerativedisorders, cognitive or memory dysfunction, Alzheimer's disease,Parkinson's disease, Huntington's disease, Amyotrophic LateralSclerosis, Gilles de la Tourettes syndrome, attention deficithyperactivity disorder, anxiety, depression, mania, manic depression,schizophrenia, obsessive compulsive disorders, eating disorders likeanorexia nervosa, bulimia and obesity, narcolepsy, nociception, memoryloss, memory dysfunction, AIDS-dementia, senile dementia, peripherialneuropathy, learning deficit, cognition deficit, attention deficit,autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia,post-traumatic syndrome, social phobia, chronic fatigue syndrome,disorders of sleep, pseudodementia, Ganser's syndrome, prementraulsyndrome, late luteal phase syndrome, chronic fatigue syndrome,premature ejaculation, erectile difficulty, mutism and trichotillomania.

The compounds of this invention may also be used in the treatment ofinflammatory conditions as for example: inflammatory skin conditionslike acne and rosacea, Chron's disease, inflammatory bowel disease,ulcerative collitis, irritable colon, diarrhoea.

Also the compounds of the invention may be used in the treatment ofdiseases associated with smooth muscle contractions as for example:convulsive disorders, angina pectoris, premature labor, convulsions,diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia.

The compounds of this invention may also be used in the treatment ofpain as for example chronic, acute and recurrent pain, postoperativepain, migraine pain or phantom limb pain; The compounds of the presentinvention may also be used for the assistance in cessation of abuse ofchemical substances as for example smoking cessation as well ascessation of use of other nicotine containing products, cessation of useof opiods like heroin, cocaine and morphine and cessation of use ofbenzodiazepines or alcohol. In the context of the present invention“treatment” means as well treatment as prevention, profylaxis andalleviation of withdrawal symptoms and abstinence as well as treatmentresulting in a voluntary diminished intake of the addictive substance.

Suitable dosage range are 0.1-500 milligrams daily, and especially 10-70milligrams daily, administered once or twice a day, dependent as usualupon the exact mode of administration, form in which administered, theindication toward which the administration is directed, the subjectinvolved and the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

I.p. means intraperetoneally, which is a well known route ofadministration. P.o. means peroral, which is a well known route ofadministration.

The invention then comprises the following alone or in combination:

The use as above wherein the disease to be treated is pain, a disease inthe central or peripheral system, a disease caused by smooth musclecontraction, neurodegeneration, inflammation, chemical substance abuseor withdrawal symptoms caused by the cessation of intake of the chemicalsubstance, such as assistance in the cessation of smoking;

The use as above wherein a disease in the central or peripheral systemis Alzheimer's disease, Parkinson's disease, memory dysfunction orattention deficit hyperactivity disorder.

The method as above wherein pain, a disease in the central or peripheralsystem, a disease caused by smooth muscle contraction,neurodegeneration, inflammation, chemical substance abuse or withdrawalsymptoms caused by the cessation of intake of chemical substances, suchas smoking cessation, is treated. The method as above wherein chemicalsubstance abuse or withdrawal symptoms caused by the cessation of intakeof the chemical substance, said chemical substance abuse being smokingor use of other nicotine containing products and withdrawal symptomscaused by cessation of use of nicotine containing products, is treated;A method as above wherein a disease in the central or peripheral system,said disease being Alzheimer's disease, Parkinson's disease, memorydysfunction or attention deficit hyperactivity disorder, is treated.

The following examples will illustrate the invention further, however,they are not to be construed as limiting.

EXAMPLES

General

All reactions involving air sensitive reagents or intermediates wereperformed under nitrogen and in anhydrous solvents. Magnesium sulfate isused as drying agent in the workup-procedures and solvents wereevaporated under reduced pressure.

Method A

4-Methyl-1-(3-pyridyl)-piperazine fumaric acid salt (1A)

A solution of 1-(3-pyridyl)-piperazine (0.35 g, 2.1 mmol), formic acid(1.0 g, 21.7 mmol), formaldehyde (0.64 g, 37%) and water (2 ml) wasstirred at reflux for 15 h. The mixture was evaporated and sodiumhydroxide (30 ml, 1 M) was added and the product was extracted threetimes with ethyl acetate (15 ml). The corre sponding salt was obtainedby addition of a diethyl ether and methanol mixture (9:1) saturated withfumaric acid. Yield 0.21 g, 34%. Mp 144.5-145.9° C.

4-Methyl-1-(3-quinolinyl)-piperazine (2A)

Was prepared according to method A. Isolated as free base. Mp 116.5-117.0° C. This compound is previously known in the literature (B.Schonen and F. Zymalkowski, Arch Pharm. (Weinheim) 314, 464-470 (1981)).

4-Methyl-1-(5-methoxy-3-pyridyl)-piperazine (3A)

Was prepared according to method A. Isolated as free base. Mp 67.5-68.0°C.

3,5-Bis-[4,4′-methyl-,1′-piperazinyl]pyridine (4A)

Was prepared according to method A. Mp 132-133° C.

1-(5-Chloro-3-pyridyl)-4-Methyl-piperazine fumaric acid salt (5A)

Was prepared according to method A. Mp 162-163° C.

4-Methyl-1-(5-phenyl-3-pyridyl)-piperazine fumaric acid salt (6A)

Was prepared according to method A. Mp 179-180° C.

1-(5-Ethoxy-3-pyridyl)-4-methyl-piperazine fumaric acid salt (7A)

Was prepared according to method A. Mp 162.2-163.7° C.

1-(5-Butoxy-3-pyridyl)-4-methyl-piperazine fumaric acid salt (8A)

Was prepared according to method A. Mp 136.9-139.2° C.

trans-4-Methyl-1-[5-(Propyl-1-en-oxy)-3-pyridyl]-piperazine fumaric acidsalt (9A)

Was prepared according to method A. Mp 145.1-145.7° C.

1-(5-Ethenyloxy-3-pyridyl)-4-methyl-piperazine fumaric acid salt (10A)

Was prepared according to method A. Mp 136.4-138.2° C.

1-(5-Methoxy-3-pyridyl)-4-methyl-1,5diazacyclooctane fumaric acid salt(11A)

Was prepared according to method A. Mp 137-139° C.

1-(6-Chloro-3-pyridazinyl)-4-methyl-1,5-diazacyclooctane fumaric acidsalt (12A)

Was prepared according to method A. Mp 166-168° C.

Method B

1-(3-Pyridyl)-piperazine fumaric acid salt (1B)

A solution of 1-(3-pyridyl)-4-tert-butoxycarbonylpiperazine (1.3 g, 4.9mmol), trifluoroacetic acid (11.3 g, 99 mmol) and dichloromethane (50ml) was stirred for 15 h. The mixture was evaporated. Sodium hydroxide(4 M) was added. The product was extracted three times withdichloromethane (50 ml) and isolated as an oil. Yield 0.72 g, 90%. Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1), saturated with fumaric acid. Mp 161.7-164.8° C.

1-(3-Quinolinyl)-piperazine (2B)

Was prepared according to method B. The reactant was obtained accordingto method C from 3-bromoquinoline. Mp 87.7-88.5° C.

1-(5-Methoxy-3-pyridyl)-piperazine fumaric acid salt (3B)

Was prepared according to method B. The reactant was obtained accordingto method C from 3-bromo-5-methoxypyridine. Mp 168.5-170.5° C.

1-(5-Chloro-3-pyridyl)-piperazine fumaric acid salt (4B)

Was prepared according to method B. The reactant was obtained accordingto method C from 3,5-dichloropyridine. Mp 195-196° C.

1-(5-Phenyl-3-pyridyl)-piperazine fumaric acid salt (5B)

Was prepared according to method B. The reactant was obtained accordingto method C from 3-bromo-5-phenylpyridine. Mp 167.5-168.5° C.

1-(5-Methoxy-3-pyridyl)-1,5-diazacyclooctane fumaric acid salt (6B)

Was prepared according to method B. The reactants were obtainedaccording to method C from 3-bromo-5-methoxypyridine and1-tert-butoxycarbonyl-(1,5-diazacyclooctane). Mp 158-160° C.

1-(6-Chloro-3-pyridazinyl)-1,5-diazacyclooctane fumaric acid salt (7B)

A mixture of 1,5-diazacyclooctane (2.07 g, 18.1 mmol),3,6-dichloropyridazine (2.70 g, 18.1 mmol) and toluene (50 ml) wasstirred at reflux overnight. Aqueous sodium hydroxide (50 ml, 1 M) wasadded followed by extraction seven times with ethyl acetate (50 ml).Chromatography on silica gel with dichloromethane, methanol and conc.ammonia (89:10:1) gave the title compound. Yield 1.72 g, 42%. Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Mp 176-178° C.

1-(6-Chloro-3-pyridazinyl)-1,4-diazacyclooctane fumaric acid salt (8B)

A mixture of 1.4-diazacyclooctane (2.07 g, 18.1 mmol), (this startingmaterial was prepared according to J. Hernandez-Mora and NadiaCordero-Antunano, Carib. J. Sci., 14, 77, 1974) 3,6-dichloropyridazine(2.70, 18.1 mmol) and toluene (50 ml) was stirred at reflux overnight.Aqueous sodium hydroxide (50 ml, 1 M) was added followed by extractionseven times with ethyl acetate (40 ml). Chromatography on silica gelwith dichloromethane, methanol and conc. ammonia (89:10:1) gave thetitle compound. Yield 1.2 g, 29%. The corresponding salt was obtained byaddition of a diethyl ether and methanol mixture (9:1) saturated withfumaric acid. Mp 177-179° C.

Method C

1-(3-Pyridyl)-4-tert-butoxycarbonyl-piperazine

A mixture of 3-bromopyridine (7.8 g, 49.4 mmol),1-tert-butoxycarbonylpiperazine (9.2 g, 49.4 mmol),tetrakis(triphenylphosphine)palladium(0) (286 mg, 0.247 mmol), potassiumtert-butoxide (11.1 g, 98.8 mmol) and anhydrous toluene (100 ml) wasstirred at 80° C. for 0.5 h. Water (100 ml) was added and the mixturewas extracted three times with ethyl acetate (75 ml). Chromatography onsilica gel with dichloromethane, methanol and conc. ammonia (89:10:1)gave the title compound as an oil. Yield 1.34 g, 10%.

Method D

1-(5-Ethoxy-3-pyridyl)piperazine fumaric acid salt (1D)

A mixture of 3-chloro-5-ethoxypyridine (6.5 g, 45.8 mmol), piperazine(19.7 g, 229 mmol), potassium tert-butoxide (11.2 g, 91.6 mmol) and1,2-dimethoxyethane (150 ml) was stirred at reflux for 1 h. Aqueoussodium hydroxide (1 M, 100 ml) was added and the mixture was extractedtwo times with ethyl acetate (150 ml). Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound. Yield 4.6 g, 48%. The corresponding salt was obtained byaddition of a diethyl ether and methanol mixture (9:1) saturated withfumaric acid. Mp 160.0-161.2° C.

1-(5-Butoxy-3-pyridyl)piperazine fumaric acid salt (2D)

Was prepared according to method D. Mp 149.4-151.7° C.

trans-1-[5-(Propyl-1-en-oxy)-3-pyridyl]-piperazine fumaric acid salt(3D)

Was prepared according to method D, from3-chloro-5-(propyl-2-en-oxy)-pyridine involving isomerization of thedouble bond. Mp 145.1-145.7° C.

1-(5-Ethenyloxy-3-pyridyl)piperazine fumaric acid salt (4D)

Was prepared according to method D. Mp 136.4-138.2° C.

1-(5-Ethoxy-3-pyridyl)-1,5-diazacyclooctane fumaric acid salt (5D)

Was prepared according to method D from 1,5-diazacyclooctane (preparedaccording to J. Hernandez-Mora “Derivatives of 1,5-diazacyclooctane”Ph.D. Dissertation, University of Michigan (1959)) at room temperatureover night. Mp 162.5-164.5° C.

1-(5-Propyloxy-3-pyridinyl)-1,5-diazacyclooctane fumaric acid salt (6D)

Was prepared according to method D from 1,5-diazacyclooctane at 70° C.over night in the presence of tetrakis(triphenylphosphine)palladium(0)(3%). Mp 150-152° C.

trans-1-[5-(Propyl-1-en-oxy)-3-pyridyl]-1,5-diazacyclooctane fumaricacid salt (7D)

Was prepared according to method D, from3-chloro-5-(propyl-2-en-oxy)-pyridine involving isomerization of thedouble bond. Mp 135-137° C.

1-(5-Ethenyloxy-3-pyridyl) 1,5-diazacyclooctane fumaric acid salt (8D)

Was prepared according to method D. Mp 142-144° C.

1-(5-Ethoxy-3-pyridyl)-4-ethyl-piperazine fumaric acid salt (9D)

A mixture of 1-(5-ethoxy-3-pyridyl)-piperazine (1.4 g, 6.8 mmol),triethylamine (0.69 g, 6.8 mmol), bromoethane (0.88 g, 8.1 mmol) anddimethylformamide (25 ml). Aqueous sodium hydroxide (1 M, 50 ml) wasadded and the mixture was extracted two times with ethyl acetate (50ml). Chromatography on silica gel with dichloromethane, methanol andconc. ammonia (89:10:1) gave the title compound. Yield 0.75 g, 47%. Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1), saturated with fumaric acid. Mp 144.8-145.9° C.

General Procedure for 3-bromo and 3-chloro-5-arylpyridines

3-Bromo-5-phenylpyridine

A mixture of 3,5-dibromopyridine (10.0 g, 42.2 mmol), phenylboronic acid(4.6 g, 38.0 mmol), tetrakis(triphenylphosphine)palladium(0) (1.45 g,1.25 mmol), potassium carbonate (17.5 g, 127 mmol), water (63 ml) and1,2-dimethoxyethane (126 ml) was stirred at reflux overnight. Aqueoussodium hydroxide (1 M, 60 ml) was added followed by extraction twicewith diethyl ether (100 ml). Chromatography on silica gel withdichloromethane as solvent gave the title compound. Yield 6.1 g, 68%, Mp42-44° C.

3-Bromo-6-thioethoxypyridine

A mixture of sodium thioethoxide (7.81 g, 92.9 mmol),2.5-dibromopyridine (20.0 g, 84.4 mmol) and dimethyl sulfoxide (100 ml).The mixture was stirred at 20° C. overnight. Sodium hydroxide (300 ml, 1M) was added and the mixture was extracted twice with diethyl ether (200ml). Chromatography on silica gel with dichloromethane:petroleum ether,1:2 as eluent, gave the title compound as an oil. Yield 16.8 g, 85%.

Method E

4-Methyl-1-(3-pyridyl)-homopiperazine (1E)

A solution of 1-(3-pyridyl)-homopiperazine (0.42 g, 2.4 mmol), formicacid (3.3 g, 71.7 mmol), formaldehyde (2.1 g, 37%) and water (10 ml) wasstirred at reflux for 15 h. The mixture was evaporated and sodiumhydroxide (15 ml, 4 M) was added and the product was extracted two timeswith ethyl acetate (15 ml). The product was obtained as an oil. Yield0.46 g,100%.

4-Methyl-1-(3-quinolinyl)-homopiperazine fumaric acid salt (2E)

Was prepared according to method E. Mp 170-171° C.

1-(5-Methoxy-3-pyridyl)-4-methyl-homopiperazine fumaric acid salt (3E)

Was prepared according to method E. Mp 145-147° C.

1-(5-Ethoxy-3-pyridyl)-4-methyl-homopiperazine fumaric acid salt (4E)

Was prepared according to method E. Mp 150-152° C.

4-Methyl-1-(5-phenyl-3-pyridyl)-homopiperazine fumaric acid salt (5E)

Was prepared according to method E. Mp 161-162° C.

1-(5-Butoxy-3-pyridyl)-4-methyl-homopiperazine fumaric acid salt (6E)

Was prepared according to method E. Mp 127-129° C.

1-(5-Methoxyethoxy-3-pyridyl)-4-methyl-homopiperazine (7E)

Was prepared according to method E. Isolated as an oil.

4-Methyl-1-[5-(2-methyl-propyloxy)-3-pyridyl]-homopiperazine fumaricacid salt (8E)

Was prepared according to method E. Mp 145.7-146.9° C.

1-(5-Cyclopropylmethoxy-3-pyridyl)-4-methyl-homopiperazine fumaric acidsalt (9E)

Was prepared according to method E. Mp 160.4-161.9° C.

4-Methyl-1-(5-propyloxy-3-pyridyl)-homopiperazine fumaric acid salt(10E)

Was prepared according to method E. Mp 148.8-153.5° C.

1-(5-Hexyloxy-3-pyridyl)-4-methyl-homopiperazine fumaric acid salt (11E)

Was prepared according to method E. Mp 128.7-130.8° C.

4-Methyl-1-[5-(3-methyl-butoxy)-3-pyridyl]-homopiperazine fumaric acidsalt (12E)

Was prepared according to method E. Mp 130.4-131.9° C.

4-Methyl-1-(6-thioethoxy-3-pyridyl)-homopiperazine fumaric acid salt(13E)

Was prepared according to method E. Mp 119-121° C.

1-(5-Cyclohexylmethoxy-3-pyridyl)-4-methyl-homopiperazine fumaric acidsalt (14E)

Was prepared according to method E. Mp 160.4-162.0° C.

4-Methyl-1-(5-pentyloxy-3-pyridyl)-homopiperazine fumaric acid salt(15E)

Was prepared according to method E. Mp 129.0-130.8° C.

1-(5-Heptyloxy-3-pyridyl)-4-methyl-homopiperazine fumaric acid salt(16E)

Was prepared according to method E. Mp 120.2-121.8° C.

trans-4-Methyl-1-(5-propyl-1-en-oxy-3-pyridyl)-homopiperazine fumaricacid salt (17E)

Was prepared according to method E. Mp 126-128° C.

4-Methyl-1-(5-thiobenzyl-3-pyridyl)-homopiperazine fumaric acid salt(18E)

Was prepared according to method E. Mp 131-133° C.

4-Methyl-1-[5-(3-pyridyl)-3-pyridyl]-homopiperazine fumaric acid salt(19E)

Was prepared according to method E. Mp 165.5-167.5° C.

4-Methyl-1-(3-nitrophenyl)-homopiperazine (20E)

Was prepared according to method E. Mp 163.1-164.4° C.

4-Methyl-1-(6-chloro-3-pyridazinyl)-homopiperazine fumaric acid salt(21E)

Was prepared according to method E. Mp 171-172° C.

4-Methyl-1-(6-phenyl-3-pyridazinyl)-homopiperazine fumaric acid salt(22E)

Was prepared according to method E. Mp 185-186° C.

4-Methyl-1-(3-pyridazinyl)-homopiperazine fumaric acid salt (23E)

Was prepared according to method E. Mp 137.8-139.3° C.

4-Methyl-1-(6-methyl-3-pyridazinyl)-homopiperazine fumaric acid salt(24E)

Was prepared according to method E. Mp 152-153° C.

1-(5-Cyclopentyloxy-3-pyridyl)-4-methyl-homopiperazine fumaric acid salt(25E)

Was prepared according to method E. Mp 123-125° C.

4-Benzyl-1-(3-Pyridyl)-homopiperazine fumaric acid salt (26E)

1-(3-Pyridyl)-homopiperazine (0.54 g, 3.0 mmol), potassium carbonate(0.42 g, 3.0 mmol), benzylbromide (0.56 g, 3.3 mmol) indimethylformamide (40 ml) was stirred at 80° C. for one hour. Water (100ml) was added and the mixture was extracted twice with ethyl acetate (25ml). Yield 0.39 g, 49%. The corresponding salt was obtained by additionof a diethyl ether and methanol mixture (9:1), saturated with fumaricacid. Mp 148.4-149.0° C.

4-Ethyl-1-(3-pyridyl)-homopiperazine fumaric acid salt (27E)

Was prepared according to 4-benzyl-1-(3-pyridyl)-homopiperazine from1-(3-pyridyl)homopiperazine. Mp 145.3-147.5° C.

Method F

1-(3-Pyridyl)-homopiperazine fumaric acid salt (1F)

A solution of 1-(3-pyridyl)-4-tert-butoxycarbonylhomopiperazine (0.91 g,3.3 mmol), trifluoroacetic acid (7.5 g, 66 mmol) and dichloromethane (30ml) was stirred for 15 h. The mixture was evaporated. Sodium hydroxide(30 ml, 4 M) was added. The product was extracted two times withdichloromethane (30 ml) and isolated as an oil. Yield 0.50 g, 85%. Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Mp 172.1-172.9° C.

1-(3-Quinolinyl)-homopiperazine fumaric acid salt (2F)

Was prepared according to method F. Mp 181-182° C.

1-(6-Methoxy-3-pyridyl)-homopiperazine fumaric acid salt (3F)

Was prepared according to method F. Mp 127-128° C.

1-(2-Chloro-5-methoxy-3-pyridyl)-homopiperazine fumaric acid salt (4F)

Was prepared according to method F. Mp 117-118° C.

1-(6-Chloro-5-methoxy-3-pyridyl)-homopiperazine fumaric acid salt (5F)

Was prepared according to method F. Mp 196-197° C.

1-(6-Bromo-5-ethoxy-3-pyridyl)-homopiperazine fumaric acid salt (6F)

Was prepared according to method F. Mp 181.7-183.2° C.

1-[6-(N-Pyrrolidinyl)-3-pyridyl]-homopiperazine fumaric acid salt (7F)

Was prepared according to method F. Mp 148.6-150.5° C.

1-(6-Phenyl-3-pyridyl)-4-homopiperazine fumaric acid salt (8F)

Was prepared according to method F. Mp 180-182° C.

1-[5-(3-Nitrophenyl)-3-pyridyl]-4-homopiperazine fumaric acid salt (9F)

Was prepared according to method F. Mp 186-188° C.

Method G

1-(3-Pyridyl)-4-tert-butoxycarbonylhomopiperazine

A mixture of 3-bromopyridine (3.95 g, 25.0 mmol),1-tert-butoxycarbonylhomopiperazine (5.0 g, 25.0 mmol),tetrakis(triphenylphosphine)palladium(0) (145 mg, 0.125 mmol), potassiumtert-butoxide (6.1 g, 50.0 mmol) and anhydrous toluene (75 ml) wasstirred at 80° C. for 4 h. Water (100 ml) was added and the mixture wasextracted three times with ethyl acetate (50 ml). Chromatography onsilica gel with dichloromethane, methanol and conc. ammonia (89:10:1)gave the title compound as an oil. Yield 0.92 g, 13%.

1-(6-Methoxy-3-pyridyl)-4-tert-butoxycarbonylhomopiperazineWas preparedaccording to Method G. Isolated as an oil.

1-(3-Quinolinyl)-4-tert-butoxycarbonylhomopiperazine

Was prepared according to Method G. Isolated as an oil.

Method H

1-(5-Methoxy-3-pyridyl)-homopiperazine fumaric acid salt (1H)

A mixture of 3-bromo-5-methoxypyridine (5.6 g, 30.0 mmol),homopiperazine (15.0 g, 150 mmol),tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.15 mmol),potassium-tert-butoxide (6.7 g, 60 mmol) and anhydrous toluene (150 ml)was stirred at 80° C. for 4 h. Water (100 ml was added and the mixturewas extracted seven times with ethyl acetate (150 ml). Chromatography onsilica gel with dichloromethane, methanol and conc. ammonia (89:10:1)gave the title compound. Yield 3.5 g, 56%. The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Mp 161-162° C.

1-(5-Phenyl-3-pyridyl)-homopiperazine fumaric acid salt (2H)

Was prepared according to method H. Mp 185-186° C.

1-(5-Ethoxy-3-pyridyl)-homopiperazine fumaric acid salt (3H)

Was prepared according to method H. Mp 157.5-159° C.

1-(5-Butoxy-3-pyridyl)-homopiperazine fumaric acid salt (4H)

Was prepared according to method H. Mp 150-151° C.

1-(5-Methoxyethoxy-3-pyridyl)-homopiperazine fumaric acid salt (5H)

Was prepared according to method H. Mp 126-127° C.

1-[5-(2-Methyl-propoxy)-3-pyridyl]-homopiperazine fumaric acid salt (6H)

Was prepared according to method H. Mp 121.9-123.3° C.

1-[5-(2-Hydroxy-ethoxy)-3-pyridyl]-homopiperazine (7H)

Was prepared according to method H. Was isolated as an oil.

1-[5-(3-Methyl-butoxy)-3-pyridyl]-homopiperazine fumaric acid salt (8H)

Was prepared according to method H. Mp 139.9-142.0° C.

1-(5-Cyclopropylmethoxy-3-pyridyl)-homopiperazine fumaric acid salt (9H)

Was prepared according to method H. Mp 154-156° C.

1-(5-Propyloxy-3-pyridyl)-homopiperazine fumaric acid salt (10H)

Was prepared according to method H. Mp 156.2-157.8° C.

1-(5-Hexyloxy-3-pyridyl)-homopiperazine fumaric acid salt (11H)

Was prepared according to method H. Mp 149.5-151.8° C.

1-(5-Cyclohexylmethoxy-3-pyridyl)-homopiperazine fumaric acid salt (12H)

Was prepared according to method H. Mp 163.3-164.5° C.

1-(6-Thioethoxy-3-pyridyl)-homopiperazine fumaric acid salt (13H)

Was prepared according to method H. Mp 115-119° C.

1-[5-(2-Ethoxy-ethoxy)-3-pyridyl]-homopiperazine fumaric acid salt (14H)

Was prepared according to method H. Mp 139.3-140.4° C.

1-(5-Pentyloxy-3-pyridyl)-homopiperazine fumaric acid salt (15H)

Was prepared according to method H. Mp 155.5-156.7° C.

1-(5-Heptyloxy-3-pyridyl)-homopiperazine fumaric acid salt (16H)

Was prepared according to method H. Mp 132.8-136.6° C.

trans-1-[5-(Propyl-1-en-oxy)-3-pyridyl]-homopiperazine fumaric acid salt(17H)

Was prepared according to method H, from3-chloro-5-(propyl-2-en-oxy)-pyridine involving isomerization of thedouble bond. Mp 124-126° C.

1-(5-Thiobenzyl-3-pyridyl)-homopiperazine fumaric acid salt (18H)

Was prepared according to method H. Mp 148-150° C.

1-(5-Carboxylamido-3-pyridyl)-homopiperazine fumaric acid salt (19H)

Was prepared according to method H. Mp 149-151° C.

1-(5-Thiophenyl-3-pyridyl)-homopiperazine fumaric acid salt (20H)

Was prepared according to method H. Mp 177-179° C.

Method I

1-[(5-Methoxy-methoxy)-3-pyridyl]-homopiperazine fumaric acid salt (1I)

A mixture of 3-chloro-5-methoxymethoxypyridine (10.0 g, 57.6 mmol),homopiperazine (28.8 g, 288 mmol),1.3-bis(diphenylphosphino)propanepalladiumdichloride (170 mg, 0.29mmol), potassium tert-butoxide (12.9 g, 115 mmol) and1,2-dimethoxyethane (100 ml) was stirred at reflux for 3 h. Sodiumhydroxide (1 M, 100 ml) was added and the mixture was extracted twotimes with ethyl acetate (150 ml). Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound as free base. Yield 9.7 g, 71%. The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Mp 129.5-131° C.

1-[5-(3-Pyridyl)-3-pyridyl]-homopiperazine fumaric acid salt (2I)

Was prepared according to method I. Mp 160-162° C.

Method J

1-(5-(1-Pyrrolyl)-3-pyridyl)-homopiperazine fumaric acid salt (1J)

A mixture of 3-chloro-5-(1-pyrrolyl)-pyridine (6.3 g, 35.3 mmol),homopiperazine (7.06 g, 70.5 mmol), potassium tert-butoxide (7.91 g,70.5 mmol) and 1,2-dimethoxyethane (100 ml) was stirred at reflux for 3h. Sodium hydroxide (1 M, 120 ml) was added and the mixture wasextracted three times with ethyl acetate (100 ml). Chromatography onsilica gel with dichloromethane, methanol and conc. ammonia (89:10:1)gave the title compound. Yield 3.45 g, 40%. The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Mp 174-175° C.

1-(5-(1-Indolyl)-3-pyridyl)-homopiperazine fumaric acid salt (2J)

Was prepared according to method J from 3-chloro-5-(1-indolyl)-pyridine.Mp 193-195° C.

1-(5,6-Dimethoxy-3-pyridyl)-homopiperazine fumaric acid salt (3J)

Was prepared according to method J from 3-chloro-5,6-dimethoxypyridine.Mp 150-152° C.

1-(5-Ethenyloxy-3-pyridyl)homopiperazine fumaric acid salt (4J)

Was prepared according to method J from 3-Chloro-5-ethenyloxypyridine.Mp 143-144° C.

1-(5-Cyclopentyloxy-3-pyridyl)homopiperazine fumaric acid salt (5J)

Was prepared according to method J. Mp 148-150° C.

1-[5-(Ethoxy-d5)-3-pyridyl]-homopiperazine fumaric acid salt (6J)

Was prepared according to method J, using3-chloro-5-(penta-deuterium-ethoxy)-pyridine as starting material. Mp163-165° C.

1-(3-Chloro-5-pyridyl)homopiperazine fumaric acid salt (7J)

Was prepared according to method J, using room temperature as reactiontemperature. Mp 144.4-146.6° C.

1-(3-Bromo-5-pyridyl)homopiperazine fumaric acid salt (8J)

Was prepared according to method J, using room temperature as reactiontemperature. Mp 180.7-185.4° C.

1-(4-Isoquinolinyl)-homopiperazine fumaric acid salt (9J)

A mixture of 4-bromoisoquinoline (0.80 g, 3.85 mmol) and homopiperazine(3.85 g, 38.5 mmol) was stirred at 170° C. overnight. Aqueous sodiumhydroxide (20 ml, 1M) was added. The mixture was extracted three timeswith ethyl acetete (30 ml). Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound. Yield 0.40 g, 46%. The corresponding salt was obtained byaddition of a diethyl ether and methanol mixture (9:1) saturated withfumaric acid. Mp 160-162° C.

3-Chloro-5-(1-pyrrolyl)-pyridine

A mixture of 3.5 dichloropyridine (10.0 g, 67.6 mmol), pyrrole (5.50 g,81.1 mmol), sodium hydride 60% (3.52 g, 87.9 mmol) and dimethylsulfoxide (50 ml) was stirred at 70° C. for 2 h. Aqueous sodiumhydroxide (200 ml, 1 M) was added and the mixture was extracted threetimes with diethyl ether (100 ml). The mixture was evaporated and,purified by chromatography on silica gel with dichloromethane andethanol (4%) as solvent. Yield 6.3 g, 52%. Mp 70.5-72.0° C.

3-Chloro-5-(1-indolyl)-pyridine

Was prepared according to 3-Chloro-5-(1-pyrrolyl)-pyridine. Yield 5.9 g,38%. Mp 56-57° C.

3-Chloro-5-ethenyloxypyridine

Thionyl chloride (58.6 g, 492.6 mmol) was added to a mixture of1[3-chloro-5-(2-hydroxyethoxy)]pyridine (14.5 g, 82.1 mmol) andtetrahydrofuran (100). The mixture was stirred for 1 h at 50° C. Themixture was evaporated. Potassium hydroxide (9.0 g, 164 mmol) andtert-butanol (100 ml) was added and the mixture was stirred for 3 daysat 100° C. The solvent was evaporated. Water (150 ml) was added andextracted twice with diethyl ether (100 ml). Yield 6.77 g, 53%.

1-(5-Hydroxy-3-pyridyl)-homopiperazine hydrochloric acid salt (10J)

1-(5-Methoxymethoxy-3-pyridyl)-homopiperazine (8.5 g, 35.9 mmol) wasstirred in hydrochloric acid (4 M, 100 ml) at room temperature for 1 h.The excess of hydrochloric acid was evaporated. A crystaline compoundwas obtained by triturating with a mixture of 5% methanol and ether.Yield 9.56 g, 100%. Mp 290-300° C.

1-(5-Trifluoromethanesulfonyl-oxy-3-pyridyl)-homopiperazine fumaric acidsalt (11J)

To a mixture of1-(5-trifluoromethanesulfonyl-oxy-3-pyridyl)-4-tert-butoxycarbonyl-homopiperazine(0.82 g, 1.9 mmol) and dichloromethane (10 ml) was added trifluoroacetic acid (2.18 g, 19.2 mmol) at room temperature. The mixture wasstirred at room temperature for 3 h. Aqueous sodium hydroxide (30 ml)was added and the mixture was extracted twice with dichloromethane (30ml). Chromatography on silica gel with dichloromethane, methanol andconc. ammonia (89:10:1) gave the title compound. The corresponding saltwas obtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Mp 154-156° C. Yield 0.29 g, 35%.

1-(5-Trifluoromethanesulfonyl-oxy-3-pyridyl)-4-tert-butoxycarbonyl-homopiperazine

To a mixture of1-(5-hydroxy-3-pyridyl)-4-tert-butoxycarbonyl-homopiperazine (4.0 g,13.6 mmol), pyridine (3.23 g, 40.8 mmol) and dichloromethane (40 ml) wasadded: triflouromethane sulfonic anhydride (3.85 g, 13.6 mmol) at 0° C.The mixture was allowed to react at room temperature overnight. Theorganic phase was washed twice with aqeous sodium hydroxide (1 M, 30ml). Chromatography on silica gel with ethyl acetate-toluene (2:1).Yield 2.26 g, 56%.

1-(5-Hydroxy-3-pyridyl)-4-tert-butoxycarbonyl-homopiperazine

A mixture of 1-(5-hydroxy-3-pyridyl)-homopiperazine hydrochloric acidsalt (15.5 g, 58.1 mmol) tert-butoxycarbonyl anhydride (12.7 g, 58.1mmol), an aqueous solution of sodium hydrogen carbonate (1 M, 290 mmol)and dichloromethane (290 ml) was stirred overnight. The organic phasewas separated and purified with chromatography on silica gel, using 6%ethanol and dichloromethane as eluent. The product was isolated as anoil. Yield 8.17 g, 48%.

1-(5-Ethynyl-3-pyridyl)-homopiperazine fumaric acid salt (12J)

A mixture of1-(5-ethynyl-3-pyridyl)-4-tert-butoxycarbonyl-homopiperazine (0.13 g,0.43 mmol), trifluoro acetic acid (0.98 g, 8.6 mmol) and dichloromethane(10 ml) was stirred for 5 h. Aqueous sodium hydroxide (1 M, 15 ml) wasadded the organic phase was separated and the aqueous phase wasextracted twice with dichloromethane (15 ml). Chromatography on silicagel with dichloromethane, methanol and conc. ammonia (89:10:1) gave thetitle compound. The corresponding salt was obtained by addition of adiethyl ether and methanol mixture (9:1) saturated with fumaric acid.Yield 30 mg, 22%. Mp 172.5-174.0° C.

1-(5-Ethynyl-3-pyridyl)-4-tert-butoxycarbonyl-homopiperazine

A mixture of1-[5-(3-methyl-3-hydroxy-butyn-1-yl)-3-pyridyl]-4-tert-butoxycarbonyl-homopiperazine(0.40 g, 1.1 mmol), sodium hydride 60% (4.5 mg, 0.11 mmol) and toluene(10 ml) was stirred at 110° C. for 3 h. The crude mixture was purifiedby chromatography on silica gel with ethyl acetate:toluene, (3:1) gavethe title compound. Yield 0.13 g, 39%.

1-[5-(3-Methyl-3-hydroxy-butyn-1-yl)-3-pyridyl]-4-tert-butoxycarbonyl-homopiperazine

A mixture of1-(5-trifluoromethanesulfonyl-oxy-3-pyridyl)-4-tert-butoxycarbonyl-homopiperazine(8.15 g, 1.9 mmol), potassium carbonate (0.66 g, 4.8 mmol), copper(I)iodide (37 mg, 0.19 mmol), palladium on carbon (5%, 10 mg),triphenylphosphine (50 mg, 0.19 mmol), lithium chloride (81 mg, 1.9mmol) and 1,2-dimethoxyethane (15 ml) was stirred at room temperaturefor 30 min. 2-Methyl-3-butyn-2-ol (1.62 g, 3.8 mmol) solved in1,2-dimethoxyethane (30 ml) was added to the mixture which was stirredat reflux overnight. The crude mixture was filtered through celite andhydrochloric acid (20 ml, 2 M) and toluene (30 ml) was added. Theorganic phase was discarded and the mixture was made alkaline withaqueous sodium hydroxide, followed by extraction with ethyl acetate (30ml). The mixture was purified by chromatography on silica gel with ethylacetate:toluene, (3:1) and gave the title compound. Yield 0.40 g, 58%.

1-(2-Chloro-5-methoxy-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine and1-(6-Chloro-5-methoxy-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine

An aqueous solution of sodium hypochlorite (16.3 ml, 8.14 mmol) wasadded to mixture of1-(5-methoxy-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine (2.5 g, 8.14mmol) and dimethylformamide (185 ml) at room temperature and stirred for0.5 h at room temperature. Water was added (300 ml) and the mixture wasextracted twice with diethyl ether (200 ml). The mixture was separatedby chromatography on silica gel with ethyl acetate:toluene (2:1). Thetitle compounds eluated in the order indicated above in in 2.0 g and 0.5g respectively, total yield 90%.

1-[5-(3-Nitrophenyl)-3-pyridyl]-4-tert-butoxycarbonylhomopiperazine(13J)

A mixture of(5-trifluoromethanesulfonyl-oxy-3-pyridyl)-4-tert-butoxycarbonyl-homopiperazine(3.0 g, 7.1 mmol), 1.3-propandiol (2.68 g, 35.3 mmol), lithium chloride(0.90 g, 21.2 mmol), potassium carbonate (10.6 ml, 2 M),tetrakis(triphenylphosphine)palladium(0) (244 mg, 0.21 mmol),3-nitrophenyl boronic acid (1.77 g, 10.6 mmol) and 1.2-dimethoxyethanewas stirred at reflux for 2 h. Aqueous sodium hydroxide was added. Themixture was extracted twice with ethyl acetate (40 ml). The mixture wasseparated by chromatography on silica gel with petroleum:ethyl acetate,(2:1). The product was isolated in quantitative yield. Mp 129-130° C.

1-(3-Nitrophenyl)-homopiperazine fumaric acid salt (14J)

A mixture of 1-fluoro-3-nitrobenzene (10.0 g, 71 mmol), andhomopiperazine (21.3 g, 213 mmol) in dioxane (100 ml) was refluxed for15 h. Water (100 ml) was added and the mixture was extracted twice withethyl acetate (100 ml). Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound. Yield 0.69 g, 4%. The corresponding salt was obtained byaddition of a diethyl ether and methanol mixture (9:1) saturated withfumaric acid. Mp 163.1-164.4° C.

1-(3-Aminophenyl)-homopiperazine fumaric acid salt (15J)

A mixture of 1-(3-nitrophenyl)-homopiperazine (2.4 g, 12.2 mmol),palladium on carbon (0.25 g, 5%) and ethanol (75 ml) was stirred underhydrogen for 24 h. The crude mixture was filtered through celite.Aqueous sodium hydroxide (50 ml, 1 M) was added and the mixture wasextracted twice with diethyl ether (50 ml). Yield 0.61 g, 26%. Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Mp 165.4-167.7° C.

1-(3-Methoxyphenyl)-homopiperazine fumaric acid salt (16J)

A mixture of 3-bromoanisole (10.0 g, 53.4 mmol), homopiperazine (10.7 g,106.9 mmol), potassium tert-butoxide (10.6 g, 106.9 mmol),tetrakis(triphenylphosphine)palladium(0) (62 mg, 0.53 mmol) and1.2-dimethoxyethane (100 ml) was stirred at reflux for 1 h.tetrakis(triphenylphosphine)palladium(0) (286 mg, 0.247 mmol) Sodiumhydroxide (1 M, 100 ml) was added and the mixture was extracted twotimes with ethyl acetate (150 ml). Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound as free base. Yield 0.79 g, 7%. The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Mp 164.1-165.7° C.

1-(3-Hydroxyphenyl)-homopiperazine fumaric acid salt (17J)

Boron tribromide (11.1 g, 44.4 mmol) was added to a mixture of1-(3-Methoxyphenyl)-homopiperazine (0.54 g, 2.8 mmol) in dichloromethane(50 ml) at −70° C. The reaction was allowed to reach room temperatureovernight. The precipitated crystals were filtered and purified bychromatography on silica gel with dichloromethane, methanol and conc.ammonia (89:10:1) gave the title compound as free base. Yield 0.22 g,41%. The corresponding salt was obtained by addition of a diethyl etherand methanol mixture (9:1) saturated with fumaric acid. Mp 165° C.,decomp.

General Procedure for 3-bromo and 3-chloro-5- or 6-alkoxypyridines

3-Bromo-5-methoxypyridine

Sodium (2.33 g, 101.3 mmol) was added to methanol (50 ml) and wasallowed to react, the mixture was evaporated. 3.5-Dibromopyridine (20.0g, 84.4 mmol) and dimethyl sulfoxide (100 ml) were added. The mixturewas stirred at 90° C. for 2 h. Sodium hydroxide (400 ml, 1 M) was addedand the mixture was extracted twice with diethyl ether (200 ml).Chromatography on silica gel with dichloromethane and 3% ethanol assolvent gave the title compound. Yield 10.6 g, 67%. Mp 30-32° C.

General Procedure for 3-bromo and 3-chloro-5-arylpyridines

3-Bromo-5-phenylpyridine

A mixture of 3,5-dibromopyridine (10.0 g, 42.2 mmol), phenylboronic acid(4.6 g, 38.0 mmol), tetrakis(triphenylphosphine)palladium(0) (1.45 g,1.25 mmol), potassium carbonate (17.5 g, 127 mmol), water (63 ml) and1,2-dimethoxyethane (126 ml) was stirred at reflux overnight. Aqueoussodium hydroxide (1 M, 60 ml) was added followed by extraction twicewith diethyl ether (100 ml). Chromatography on silica gel withdichloromethane as solvent gave the title compound. Yield 6.1 g, 68%, Mp42-44° C.

3-Bromo-6-thioethoxypyridine

A mixture of sodium thioethoxide (7.81 g, 92.9 mmol),2.5-Dibromopyridine (20.0 g, 84.4 mmol) and dimethyl sulfoxide (100 ml).The mixture was stirred at 20° C. overnight. Sodium hydroxide (300 ml, 1M) was added and the mixture was extracted twice with diethyl ether (200ml). Chromatography on silica gel with dichloromethane:petroleum ether,(1:2) as eluent, gave the title compound as an oil. Yield 16.8 g, 85%.

3-Bromo-5-thioethoxypyridine

Prepared according to 3-Bromo-6-thioethoxypyridine, using 40° C. asreaction temperature. The title compound was obtained as an oil

Method K

1-(6-Chloro-3-pyridazinyl)-homopiperazine fumaric acid salt (1K)

A mixture of 3,6-dichloropyridazine (5.0 g, 33.5 mmol), homopiperazine(3.36 g, 33.5 mmol) and 50 ml of toluene was stirred at reflux for 0.5h. Sodium hydroxide (50 ml, 1 M) was added and the mixture was extractedthree times with ethyl acetate (100 ml). Chromatography on silica gelwith dichloromethane, methanol and conc. ammonia (89:10:1) gave thetitle compound as free base. Yield 2.2 g, 31%. The corresponding saltwas obtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Mp 165-166° C.

1-(6-Phenyl-3-pyridazinyl)-homopiperazine fumaric acid salt (2K)

Was prepared according to method K from 2-chloro-6-phenylpyridazine. Mp187-189° C.

1-(6-Chloro-2-pyrazinyl)-homopiperazine fumaric acid salt (3K)

Was prepared according to method K from 2,6-dichloropyrazine. Mp180-181° C.

1-(3,6-Dimethyl-2-pyrazinyl)-homopiperazine fumaric acid salt (4K)

Was prepared according to method K, in the absence of solvent from2-chloro-3,6-dimethylpyrazine at 130° C. Mp 149-151° C.

1-(6-Methyl-3-pyridazinyl)-homopiperazine fumaric acid salt (5K)

Was prepared according to method K in the absence of solvent at 130° C.from 3-chloro-6-methyl-pyridazine. Mp 102-105° C.

1-(5-Triflouromethyl-3-pyridyl)-homopiperazine fumaric acid salt (6K)

Was prepared according to method K in the absence of solvent at 140° C.overnight from 3-chloro-5-trifluoromethylpyridine. Mp 164-166° C.

1-(3-Chloro-2-quinoxalinyl)-homopiperazine fumaric acid salt (7K)

Was prepared according to method K in the absence of solvent at 130° C.for 4 h from 2.3-dichloroquinoxaline. Mp 136.2-139.9° C.

1-(6-Bromo-3-pyridyl)-homopiperazine fumaric acid salt (8K)

1-(3-Pyridyl)-homopiperazine (0.885 g, 5.0 mmol) was solved inacetonitrile (50 ml). N-Bromosuccinimide (1.7 g, 10.0 mmol) was added,and the mixture was stirred for 15 min. The crude mixture wasevaporated. Chromatography on silica gel with dichloromethane, methanoland conc. ammonia (89:10:1) gave the title compound as free base. Yield0.50 g, 39%. The corresponding salt was obtained by addition of adiethyl ether and methanol mixture (9:1) saturated with fumaric acid. Mp164-166° C.

1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine

1-(3-Pyridyl)-4-tert-butoxycarbonyl homopiperazine (25.0 g, 90.1 mmol)was solved in acetonitrile (400 ml) and cooled to 0° C.N-Bromosuccinimide (19.3 g, 108.2 mmol) was added during 10 min. Water(400 ml) was added and the mixture was extracted twice with diethylether (200 ml). Chromatography on silica gel with a mixture ofpetroleum:ethyl acetate (1:1) gave the title compound as free base.Yield 18.7 g, 58%.

1-(6-Chloro-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine

A stirred solution of 1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine (3.6 g, 10 mmol) in tetrahydrofuran (200 ml) was cooledto −78° C. Tert-butyllithium (14.7 ml, 1.5 M) in pentane was addedduring 10 min, followed by stirring for 5 min at −78° C.1,3-Dichloro-5,5-dimethylhydantoin (1.97 g, 10 mmol) was added in smallportions. The mixture was stirred for 0.5 min. Aqueous sodium hydroxidewas added (100 ml, 4 M), and the reaction was allowed reach roomtemperature. The mixture was extracted twice with diethyl ether (100 ml)Chromatography on silica gel with a mixture of petroleum:ethyl acetate(1:1) gave the title compound as free base. Yield 1.7 g, 55%.

1-(6-Chloro-3-pyridyl)-homopiperazine (9K)

A mixture of 1-(6-chloro-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine(1.7 g, 5.5 mmol), trifluoro acetic acid (4.5 ml, 55 mmol) anddichloromethane at room temperature for 1 h. The mixture was evaporated.Chromatography on silica gel with a mixture of petroleum:ethyl acetate(1:1) gave the title compound as free base. The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Mp 165-167° C. Yield 0.72 g, 40%.

1-[6-(N-Pyrrolidinyl)-3-pyridyl]-4-tert-butoxycarbonyl homopiperazine

A stirred solution of 1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine (0.71 g, 2.0 mmol), pyrrolidine (2.0 g, 20 mmol),potassium tert-butoxide (0.45 g, 4.0 mmol),tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) and1.2-dimethoxyethane was stirred at reflux overnight. Water (40 ml) wasadded and the mixture was extracted twice with ethyl acetate (20 ml)Chromatography on silica gel with a mixture of petroleum:ethyl acetate(1:1) gave the title compound as free base. Yield 0.21 g, 30%.

1-(6-phenyl-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (10K)

1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (0.89 g, 2.5mmol), phenyl boronic acid (0.37 g, 3.0 mmol),tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.12 mmol),1.2-dimethoxyethane (50 ml), potassium carbonate (1.0 g, 7.5 mmol) andwater (7.5 ml) was stirred at reflux overnight. Water (50 ml) was addedand the mixture was extracted twice with ethyl acetate (40 ml).Chromatography on silica gel with a mixture of petroleum:ethyl acetate(1:1) gave the title compound as an oil. Yield 0.83 g. 94%.

1-(6-Bromo-5-ethoxy-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine

N-Bromosuccinimide (2.7 g, 15.2 mmol) was added to1-(5-Ethoxy-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (4.5 g, 14.0mmol) at room temperature. The mixture was stirred for 2 min. Themixture was washed with saturated sodium sulfite (100 ml) was.Chromatography on silica gel with a mixture of petroleum:ethyl acetate(1:1) gave the title compound as an oil. Yield 3.3 g, 58%.

Method L

1-(3-Pyridazinyl)-homopiperazine (1L)

A mixture of 1-(3-Chloro-6-pyridazinyl)-homopiperazine (5.56 g, 26.1mmol), palladium on carbon (2.1 g, 10%) and ethanol (150 ml) was stirredunder hydrogen overnight. The crude product was filtered through celiteand evaporated. Chromatography on silica gel with dichloromethane,methanol and conc. ammonia (89:10:1) gave the title compound as freebase. Yield 2.78 g, 60%, 185.0-186.9° C.

1-(2-Quinoxalinyl)-homopiperazine fumaric acid salt (2L)

Was prepared according to method L from1-(3-Chloro-2-quinoxalinyl)-homopiperazine Mp 177-180° C.

N-(5-Methoxy-3-pyridyl)-ethylenediamine (3L)

Sodium (4.98 g, 216.7 mmol) was added to methanol (100 ml), and wasallowed to react, the mixture was evaporated. 3.5-Dichloropyridine (25.0g, 166.7 mmol) and dimethyl sulfoxide (250 ml) were added. The mixturewas stirred at 70° C. overnight. Aqueous sodium hydroxide (500 ml, 1 M)was added, and the mixture was extracted twice with diethyl ether (500ml). The crude mixture was stirred together with ethylenediamine (50.0g, 833.5 mmol), potassium tert-butoxide (37.4 g, 333.4 mmol) and1,2-dimethoxyethane (500 ml) at reflux for 4 h. Aqueous sodium hydroxide(1 l, 1 M) was added, and the mixture was extracted five times withethyl acetate (500 ml). Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound as free base. Yield 13.0 g, 47%.

Method M

1-(5-Methoxy-3-pyridyl)-3-methyl-imidazolidine fumaric acid salt (1M)

A mixture of N-(5-methoxy-3-pyridyl)-ethylenediamine (0.76 g, 4.5 mmol),formic acid (6.3 g, 136.4 mmol) and formaldehyde (4.1 g, 136.4 mmol) wasstirred at reflux for 2 h at reflux. The crude mixture was evaporated.Sodium hydroxide (50 ml, 4 M) was added and the mixture was extractedwith ethyl acetate. Chromatography on silica gel with dichloromethane,methanol and conc. ammonia (89:10:1) gave the title compound as freebase. Yield 9.7 g, 44%. The corresponding salt was obtained by additionof a diethyl ether and methanol mixture (9:1) saturated with fumaricacid. Mp 139-142° C.

1-(5-Methoxy-3-pyridyl)-3-methyl-1.3-diazacyclohexane fumaric acid salt(2M)

Was prepared according to method M fromN-(5-methoxy-3-pyridyl)-1,3-propylene-diamine. Mp 149-151° C.

What is claimed is:
 1. A compound represented by the formula

any of its enantiomers or any mixture of enantiomers, isotopes thereof,or a pharmaceutically acceptable salt thereof; wherein R representshydrogen, C₁₋₈-alkyl, C₃₋₇-cycloalkyl, or C₃₋₇-cycloalkyl-C₁₋₈-alkyl;and R¹ represents a substituted phenyl selected from the groupconsisting of aminophenyl, nitrophenyl, hydroxyphenyl, andC₁₋₈-alkoxyphenyl; or R¹ represents a 3-pyridyl or a 2-pyrazinyl group,which group may be substituted one or more times with substituentsselected from the group consisting of C₁₋₈-alkyl, C₂₋₆-alkynyl,C₁₋₈-alkoxy, methoxymethoxy, methoxyethoxy, ethoxyethoxy,C₃₋₇-cycloalkoxy, C₂₋₆-alkenoxy, hydroxy-C₁₋₈-alkoxy, C₁₋₈alkylthio,halogen, hydroxy, CF₃, trifluoromethanesulfonyloxy, carboxamido, phenyl,nitrophenyl, pyrrolidinyl, pyridyl, pyrrolyl, and indolyl; or R¹represents a 3-quinolinyl group.
 2. The compound according to claim 1,wherein R represents hydrogen or C₁₋₈-alkyl.
 3. The compound accordingto claim 1, wherein R¹ represents: 4-isoquinolinyl; or a 3-pyridyl or a3-quinolinyl group, which group may optionally be substituted one ormore times with C₁₋₈-alkoxy, methoxymethoxy, methoxyethoxy,ethoxyethoxy, hydroxy-C₁₋₈-alkoxy, C₁₋₈-alkylthio, C₂₋₆-alkenoxy,carboxamido, indolyl, hydroxy, trifluoro-methanesulfonyloxy, or halogen;or with phenyl, which phenyl is optionally substituted with nitro; orwith a pyrrolidinyl, pyridyl, pyrrolyl, or indolyl group.
 4. A method oftreating withdrawal symptoms caused by smoking cessation, which methodcomprises the step of administering to a mammal afflicted with suchdisease a therapeutically effective amount of a compound according toclaim
 1. 5. The homopiperazine compound according to claim 1, wherein R¹represents 3-nitrophenyl, 3-aminophenyl, 3-methoxyphenyl, or3-hydroxyphenyl.
 6. The homopiperazine compound according to claim 5,which is 4-methyl-1-(3-nitrophenyl)-homopiperazine,1-3-(nitrophenyl)-homopiperazine, 1-(3-(aminophenyl)-homopiperazine,1-3-(methoxyphenyl)-homopiperazine, 1-(3-(hydroxyphenyl)-homopiperazine,or any of its enantiomers or any mixture of enantiomers, isotopesthereof, or a pharmaceutically acceptable salt thereof.
 7. The compoundaccording to claim 1, wherein R¹ represents a 3-pyridyl or a 2-pyrazinylgroup, which group may be substituted one or more times withsubstituents selected from the group consisting of C₁₋₈-alkyl,C₁₋₈-alkoxy, methoxymethoxy, methoxyethoxy, ethoxyethoxy,C₃₋₇-cycloalkoxy, C₂₋₆-alkenoxy, C₂₋₆-alkynyl, hydroxy-C₁₋₈-alkoxy,C₁₋₈-alkylthio, halogen, hydroxy, CF₃, trifluoromethanesulfonyloxy,carboxamido, phenyl, nitrophenyl, pyrrolidinyl, pyridyl, pyrrolyl, andindolyl.
 8. The compound according to claim 1, wherein R¹ represents3-pyridyl, 5-methoxy-3-pyridyl, 5-chloro-3-pyridyl, 5-ethoxy-3-pyridyl,6-methoxy-3-pyridyl, 5-propyloxy-3-pyridyl, 5-phenyl-3-pyridyl,5-(2-methyl-propyloxy)-3-pyridyl, 5-propyl-1-en-oxy-3-pyridyl,2-chloro-5-methoxy-3-pyridyl, 6-chloro-5-methoxy-3-pyridyl,6-bromo-5-ethoxy-3-pyridyl, 6-(N-pyrrolidinyl)-3-pyridyl,6-phenyl-3-pyridyl, 5-(3-nitrophenyl)-3-pyridyl, 5-butoxy-3-pyridyl,5-methoxyethoxy-3-pyridyl, 5-(2-methyl-propoxy)-3-pyridyl,5-(2-hydroxy-ethoxy)-3-pyridyl, 5-(3-methyl-butoxy)-3-pyridyl,5-cyclopropylmethoxy-3-pyridyl, 5-propyloxy-3-pyridyl,5-hexyloxy-3-pyridyl, 5-cyclohexylmethoxy-3-pyridyl,6-thioethoxy-3-pyridyl, 5-(2-ethoxyethoxy)-3-pyridyl,5-pentyloxy-3-pyridyl, 5-heptyloxy-3-pyridyl,5-(propyl-1-en-oxy)-3-pyridyl, 5-carboxamido-3-pyridyl,5-methoxy-3-pyridyl, 5-(3-pyridyl)-3-pyridyl, 5-(1-pyrrolyl)-3-pyridyl,5-(1-indolyl)-3-pyridyl, 5,6-dimethoxy-3-pyridyl,5-ethenyloxy-3-pyridyl, 5-cyclopentyloxy-3-pyridyl,5-(ethoxy-d5)-3-pyridyl, 3-chloro-5-pyridyl, 3-bromo-5-pyridyl,5-hydroxy-3-pyridyl, 5-trifluoromethanesulfonyl-oxy-3-pyridyl,5-ethynyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl, 6-bromo-3-pyridyl, or6-chloro-3-pyridyl.
 9. The compound according to claim 8, which is:4-Methyl-1-(3-pyridyl)-homopiperazine;1-(5-Methoxy-3-pyridyl)-4-methyl-homopiperazine;1-(5-Ethoxy-3-pyridyl)-4-methyl-homopiperazine;4-Methyl-1-(5-phenyl-3-pyridyl)-homopiperazine;1-(5-Butoxy-3-pyridyl)-4-methyl-homopiperazine;1-(5-Methoxyethoxy-3-pyridyl)-4-methyl-homopiperazine;4-Methyl-1-[5-(2-methyl-propyloxy)-3-pyridyl]-homopiperazine;1-(5-Cyclopropylmethoxy-3-pyridyl)-4-methyl-homopiperazine;4-Methyl-1-(5-propyloxy-3-pyridyl)-homopiperazine;1-(5-Hexyloxy-3-pyridyl)-4-methyl-homopiperazine;4-Methyl-1-[5-(3-methyl-butoxy)-3-pyridyl]-homopiperazine;4-Methyl-1-(6-thioethoxy-3-pyridyl)-homopiperazine;1-(5-Cyclohexylmethoxy-3-pyridyl)-4-methyl-homopiperazine;4-Methyl-1-(5-pentyloxy-3-pyridyl)-homopiperazine;1-(5-Heptyloxy-3-pyridyl)-4-methyl-homopiperazine;4-Methyl-1-(5-propyl-1-en-oxy-3-pyridyl)-homopiperazine;4-Methyl-1-[5-(3-pyridyl)-3-pyridyl]-homopiperazine;1-(5-Cyclopentyloxy-3-pyridyl)-4-methyl-homopiperazine;4-Benzyl-1-(3-pyridyl)-homopiperazine;4-Ethyl-1-(3-pyridyl)-homopiperazine; 1-(3-Pyridyl)-homopiperazine;1-(6-Methoxy-3-pyridyl)-homopiperazine;1-(2-Chloro-5-methoxy-3-pyridyl)-homopiperazine;1-(6-Chloro-5-methoxy-3-pyridyl)-homopiperazine;1-(6-Bromo-5-ethoxy-3-pyridyl)-homopiperazine;1-[6-(N-Pyrrolidinyl)-3-pyridyl]-homopiperazine;1-(6-Phenyl-3-pyridyl)-4-homopiperazine;1-[5-(3-Nitrophenyl)-3-pyridyl]-4-homopiperazine;1-(5-Methoxy-3-pyridyl)-homopiperazine;1-(5-Phenyl-3-pyridyl)-homopiperazine;1-(5-Ethoxy-3-pyridyl)-homopiperazine;1-(5-Butoxy-3-pyridyl)-homopiperazine;1-(5-Methoxyethoxy-3-pyridyl)-homopiperazine;1-[5-(2-Methyl-propoxy)-3-pyridyl]-homopiperazine;1-[5-(2-Hydroxy-ethoxy)-3-pyridyl]-homopiperazine;1-[5-(3-Methyl-butoxy)-3-pyridyl]-homopiperazine;1-(5-Cyclopropylmethoxy-3-pyridyl)-homopiperazine;1-(5-Propyloxy-3-pyridyl)-homopiperazine;1-(5-Hexyloxy-3-pyridyl)-homopiperazine;1-(5-Cyclohexylmethoxy-3-pyridyl)-homopiperazine;1-(6-Thioethoxy-3-pyridyl)-homopiperazine;1-[5-(2-Ethoxy-ethoxy)-3-pyridyl]-homopiperazine;1-(5-Pentyloxy-3-pyridyl)-homopiperazine;1-(5-Heptyloxy-3-pyridyl)-homopiperazine;1-[5-(Propyl-1-en-oxy)-3-pyridyl]-homopiperazine;1-(5-Carboxylamido-3-pyridyl)-homopiperazine;1-[(5-Methoxy-methoxy)-3-pyridyl]-homopiperazine;1-[5-(3-Pyridyl)-3-pyridyl]-homopiperazine;1-(5-(1-Pyrrolyl)-3-pyridyl)-homopiperazine;1-(5-(1-Indolyl)-3-pyridyl)-homopiperazine;1-(5,6-Dimethoxy-3-pyridyl)-homopiperazine;1-(5-Ethenyloxy-3-pyridyl)homopiperazine;1-(5-Cyclopentyloxy-3-pyridyl)homopiperazine;1-[5-(Ethoxy-d5)-3-pyridyl]-homopiperazine;1-(3-Chloro-5-pyridyl)homopiperazine;1-(3-Bromo-5-pyridyl)homopiperazine;1-(5-Hydroxy-3-pyridyl)-homopiperazine;1-(5-Trifluoromethanesulfonyl-oxy-3-pyridyl)-homopiperazine;1-(5-Ethynyl-3-pyridyl)-homopiperazine;1-(5-Triflouromethyl-3-pyridyl)-homopiperazine;1-(6-Bromo-3-pyridyl)-homopiperazine; or1-(6-Chloro-3-pyridyl)-homopiperazine; or any of its enantiomers or anymixture of enantiomers, isotopes thereof, or a pharmaceuticallyacceptable addition salt thereof.
 10. The compound according to claim 1,wherein R¹ represents 6-chloro-2-pyrazinyl or 3,6-dimethyl-2-pyrazinyl.11. The homopiperazine compound according to claim 10, which is1-(6-Chloro-2-pyrazinyl)-homopiperazine;1-(3,6-Dimethyl-2-pyrazinyl)-homopiperazine; or any of its enantiomersor any mixture of enantiomers, isotopes thereof, or a pharmaceuticallyacceptable addition salt thereof.
 12. The compound according to claim 1,wherein R¹ represents 3-quinolinyl.
 13. The pharmaceutical compositionaccording to claim 3, formulated for topical administration to theepidermis as an ointment, a cream, or a lotion, or as a transdermalpatch.
 14. A compound selected from the group consisting of:1-(5-Methoxyethoxy-3-pyridyl)-4-methyl-homopiperazine;1-(5-Methoxyethoxy-3-pyridyl)-homopiperazine;1-[5-(2-Ethoxyethoxy)-3-pyridyl]-homopiperazine;1-[(5-Methoxymethoxy)-3-pyridyl]-homopiperazine; and any of itsenantiomers or any mixture of enantiomers, isotopes thereof or apharmaceutically acceptable salt thereof.